N-(3-amino-2-hydroxy-propyl) substituted alkylamide compounds

ABSTRACT

Disclosed are compounds of the formula (I): 
     
       
         
         
             
             
         
       
     
     useful in treating Alzheimer&#39;s disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer&#39;s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

This application is a divisional of U.S. application Ser. No.11/296,669, filed Dec. 7, 2005, now U.S. Pat. No. 7,589,094; which is adivisional of U.S. application Ser. No. 10/193,044, filed Jul. 11, 2002,now abandoned; which claims the benefit of U.S. Provisional PatentApplication No. 60/304,525, filed Jul. 11, 2001; U.S. Provisional PatentApplication No. 60/308,756, filed Jul. 30, 2001; U.S. Provisional PatentApplication No. 60/341,341, filed Dec. 17, 2001; U.S. Provisional PatentApplication No. 60/341,416, filed Dec. 17, 2001; U.S. Provisional PatentApplication No. 60/344,872, filed Dec. 21, 2001; and U.S. ProvisionalPatent Application No. 60/380,574, filed Dec. 21, 2001.

The sequence listing is filed with the application in electronic formatonly and is incorporated by reference herein. The sequence listing textfile “01-1733-D1-DIV_SequenceListing.txt” was created on Aug. 27, 2009,and is 4,611 bytes in size.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to N-(3-amino-2-hydroxy-propyl)-aryl-,heteroaryl-, cycloalkyl- and heterocyclyl-alkylamide compounds and suchcompounds that are useful for the treatment of Alzheimer's disease. Morespecifically, the invention relates to such compounds that are capableof inhibiting beta-secretase, an enzyme that cleaves amyloid precursorprotein to produce amyloid beta peptide (A beta), a major component ofthe amyloid plaques found in the brains of Alzheimer's sufferers.

2. Description of the Related Art

Alzheimer's disease (AD) is a progressive degenerative disease of thebrain primarily associated with aging. Clinical presentation of AD ischaracterized by loss of memory, cognition, reasoning, judgment, andorientation. As the disease progresses, motor, sensory, and linguisticabilities are also affected until there is global impairment of multiplecognitive functions. These cognitive losses occur gradually, buttypically lead to severe impairment and eventual death in the range offour to twelve years.

Alzheimer's disease is characterized by two major pathologicobservations in the brain: neurofibrillary tangles and beta amyloid (orneuritic) plaques, comprised predominantly of an aggregate of a peptidefragment know as A beta. Individuals with AD exhibit characteristicbeta-amyloid deposits in the brain (beta amyloid plaques) and incerebral blood vessels (beta amyloid angiopathy) as well asneurofibrillary tangles. Neurofibrillary tangles occur not only inAlzheimer's disease but also in other dementia-inducing disorders. Onautopsy, large numbers of these lesions are generally found in areas ofthe human brain important for memory and cognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloidogenic plaques and vascular amyloid angiopathy alsocharacterize the brains of individuals with Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type (HCHWA-D), and other neurodegenerative disorders.Beta-amyloid is a defining feature of AD, now believed to be a causativeprecursor or factor in the development of disease. Deposition of A betain areas of the brain responsible for cognitive activities is a majorfactor in the development of AD. Beta-amyloid plaques are predominantlycomposed of amyloid beta peptide (A beta, also sometimes designatedbetaA4). A beta peptide is derived by proteolysis of the amyloidprecursor protein (APP) and is comprised of 39-42 amino acids. Severalproteases called secretases are involved in the processing of APP.

Cleavage of APP at the N-terminus of the A beta peptide bybeta-secretase and at the C-terminus by one or more gamma-secretasesconstitutes the beta-amyloidogenic pathway, i.e. the pathway by which Abeta is formed. Cleavage of APP by alpha-secretase produces alpha-sAPP,a secreted form of APP that does not result in beta-amyloid plaqueformation. This alternate pathway precludes the formation of A betapeptide. A description of the proteolytic processing fragments of APP isfound, for example, in U.S. Pat. Nos. 5,441,870; 5,721,130; and5,942,400.

An aspartyl protease has been identified as the enzyme responsible forprocessing of APP at the beta-secretase cleavage site. Thebeta-secretase enzyme has been disclosed using varied nomenclature,including BACE, Asp, and Memapsin. See, for example, Sindha et al.,1999, Nature 402:537-554 (p 501) and published PCT applicationWO00/17369.

Several lines of evidence indicate that progressive cerebral depositionof beta-amyloid peptide (A beta) plays a seminal role in thepathogenesis of AD and can precede cognitive symptoms by years ordecades. See, for example, Selkoe, 1991, Neuron 6:487. Release of A betafrom neuronal cells grown in culture and the presence of A beta incerebrospinal fluid (CSF) of both normal individuals and AD patients hasbeen demonstrated. See, for example, Seubert et al., 1992, Nature359:325-327.

It has been proposed that A beta peptide accumulates as a result of APPprocessing by beta-secretase, thus inhibition of this enzyme's activityis desirable for the treatment of AD. In vivo processing of APP at thebeta-secretase cleavage site is thought to be a rate-limiting step in Abeta production, and is thus a therapeutic target for the treatment ofAD. See for example, Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1-19.

BACE1 knockout mice fail to produce A beta, and present a normalphenotype. When crossed with transgenic mice that over express APP, theprogeny show reduced amounts of A beta in brain extracts as comparedwith control animals (Luo et al., 2001 Nature Neuroscience 4:231-232).This evidence further supports the proposal that inhibition ofbeta-secretase activity and reduction of A beta in the brain provides atherapeutic method for the treatment of AD and other beta amyloiddisorders.

At present there are no effective treatments for halting, preventing, orreversing the progression of Alzheimer's disease. Therefore, there is anurgent need for pharmaceutical agents capable of slowing the progressionof Alzheimer's disease and/or preventing it in the first place.

Compounds that are effective inhibitors of beta-secretase, that inhibitbeta-secretase-mediated cleavage of APP, that are effective inhibitorsof A beta production, and/or are effective to reduce amyloid betadeposits or plaques, are needed for the treatment and prevention ofdisease characterized by amyloid beta deposits or plaques, such as AD.

SUMMARY OF THE INVENTION

The invention provides compounds of formula (I):

wherein

-   m is 0-5;-   B is aryl or heteroaryl optionally substituted with one, two, three    or four groups independently selected from R₆, R′₆, R″₆ and R′″₆, or-   B is cycloalkyl or heterocycloalkyl optionally substituted with one,    two, three, four, five, six, seven or eight groups independently    selected from R_(6a), R_(6b), R′_(6a), R′_(6b), R″_(6a), R″_(6b),    R′″_(6a) and R′″_(6b);-   R₄ and R₁₄ independently are H, —NRR′, —SR, —CN, —OCF₃, —CF₃,    —CONRR′, —CO₂R, —SO₂NRR′, —O—P(═O)(OR)(OR′), —N(R)—C(═O) (R′), —N(R)    (SO₂R′), —SO₂R, —C(═O)R, —NO₂, halogen, —(CH₂)₀₋₄-aryl,    —(CH₂)₀₋₄-heteroaryl, or    -   C₁-C₈ alkyl, C₂-C₇ alkenyl or C₂-C₇ alkynyl, each of which is        optionally substituted with one, two or three groups selected        from —NRR′, —SR, —CN, —OCF₃, —CF₃, —CONRR′, —CO₂R, —SO₂NRR′,        —O—P(═O) (OR) (OR′), —N(R)—C(═O) (R′), —N(R) (SO₂R′), —SO₂R,        —C(═O)R, —NO₂, halogen, —(CH₂)₀₋₄-aryl, and        —(CH₂)₀₋₄-heteroaryl, or-   R₄ and R₁₄ together are oxo;-   R″₄ and R′″₄ independently are H, —OR, —NRR′, —SR, —CN, —OCF₃, —CF₃,    —CONRR′, —CO₂R, —SO₂NRR′, —O—P(═O)(OR)(OR′), —N(R)—C(═O)(R′), —N(R)    (SO₂R′), —SO₂R, —C(═O)R, —NO₂, halogen, —(CH₂)₀₋₄-aryl,    —(CH₂)₀₋₄-heteroaryl, or    -   C₁-C₈ alkyl, C₂-C₇ alkenyl or C₂-C₇ alkynyl, each of which is        optionally substituted with one, two or three groups selected        from —OR, —NRR′, —SR, —CN, —OCF₃, —CF₃, —CONRR′, —CO₂R,        —SO₂NRR′, —O—P(═O)(OR)(OR), —N(R)—C(═O)(R′), —N(R)(SO₂R′),        —SO₂R, —C(═O)R, —NO₂, halogen, —(CH₂)₀₋₄-aryl, and        —(CH₂)₀₋₄-heteroaryl, or-   R″₄ and R′″₄ together are oxo;-   R and R′ independently are —H, —(C₁-C₁₀) alkyl, —(CH₂)₀₋₄—R_(aryl),    —(CH₂)₀₋₄—R_(heteroaryl), —(CH₂)₀₋₄—R_(heterocyclyl), or    -   C₂-C₇ alkenyl or C₂-C₇ alkynyl, each of which is optionally        substituted with one, two or three substituents selected from        the group consisting of halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃        alkoxy, amino, mono- or dialkylamino, and C₁-C₆ alkyl, or    -   —(CH₂)₀₋₄—C₃-C₇ cycloalkyl optionally substituted with one, two        or three substituents selected from the group consisting of        halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, mono- or        dialkylamino, and C₁-C₆ alkyl;-   R₁ is —(CH₂)₁₂—S(O)₀₋₂—(C₁-C₆ alkyl), or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from halogen, —OH, ═O, —SH, —C≡N, —CF₃,        —C₁-C₃ alkoxy, amino, mono- or dialkylamino, —N(R)C(O)R′—,        —OC(═O)-amino and —OC(═O)-mono- or dialkylamino, or    -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally        substituted with 1, 2, or 3 groups independently selected from        halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or        dialkylamino, or    -   aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl, —C₁-C₆        alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ring        portions of each are optionally substituted with 1, 2, 3, or 4        groups independently selected from halogen, —OH, —SH, —C≡N,        —NR₁₀₅R′₁₀₅, —CO₂R, —N(R)COR′, or —N(R)SO₂R′, —C(═O)— (C₁-C₄)        alkyl, —SO₂-amino, —SO₂-mono or dialkylamino, —C(═O)-amino,        —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄) alkyl, or        -   C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups            which are independently selected from halogen, or        -   C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3            groups independently selected from halogen, —OH, —SH, —C≡N,            —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyl and mono- or            dialkylamino, or        -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups            independently selected from halogen, —OH, —SH, —C≡N, —CF₃,            —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃            alkyl, or        -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally            substituted with 1, 2, or 3 groups independently selected            from halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino,            C₁-C₆ alkyl and mono- or dialkylamino; and the heterocyclyl            group is optionally further substituted with oxo;-   R₆, R′6, R″₆, R′″₆, R_(6a), R_(6b), R′_(6a), R″_(6b), R″_(6a),    R″_(6b), R′″_(6a) and R′″_(6b) independently are —OR, —NO₂, halogen,    —CO₂R, —C≡N, —NRR′, —SR, —SO₂R, —C(═O)R, —OCF₃, —CF₃, —CONRR′,    —SO₂NRR′, —O—P(═O) (OR) (OR′), —N(R) (COR′), —N(R) (SO₂R′),    —(CH₂)₀₋₄—CO—NR₇R′ 7, —(CH₂)₀₋₄—O— (CH₂)₀₋₄—CONRR′, —(CH₂)₀₋₄—CO—    (C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO— (C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO—    (C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl),    —(CH₂)₀₋₄—R_(aryl), —(CH₂)₀₋₄—R_(heteroaryl),    —(CH₂)₀₋₄—R_(heterocyclyl), —(CH₂)₀₋₄—CO—R_(aryl),    —(CH₂)₀₋₄—CO—R_(heteroaryl), —(CH₂)₀₋₄—CO—R_(heterocyclyl),    —(CH₂)₀₋₄—CO—R₁₀, —(CH₂)₀₋₄—CO—O—R₁₁, —(CH₂)₀₋₄—SO₂—NR₇R′₇,    —(CH₂)₀₋₄—SO— (C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂— (C₁-C₁₂ alkyl),    —(CH₂)₀₋₄—SO₂— (C₃-C₇ cycloalkyl), —(CH₂)₄—N(H or R₁₁)—CO—O—R₁₁,    —(CH₂)₀₋₄—N(H or R₁₁)—CO—N(R₁₁)₂, —(CH₂)₀₋₄—N(H or R₁₁)—CS—N(R₁₁)₂,    —(CH₂)₀₋₄—N(—H or R₁₁)—CO—R₇, —(CH₂)₀₋₄—NR₇R′₇, —(CH₂)₀₋₄—R₁₀,    —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)— (O—R_(aryl))₂,    —(CH₂)₀₋₄—O—CO—N(R₁₁)₂, —(CH₂)₀₋₄—O—CS—N(R₁₁)₂, —(CH₂)₀₋₄—O(R₁₁),    —(CH₂)₀₋₄—O— (R₁₁)—COOH, —(CH₂)₀₋₄—S—(R₁₁), C₃-C₇ cycloalkyl,    —(CH₂)₀₋₄—N(—H or R₁₁)—SO₂—R₇, or —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, or    -   C₁-C₈ alkyl optionally substituted with one, two or three groups        independently selected from C₁-C₆ alkyl, —F, —Cl, —Br, —I, —OR,        —NO₂, —F, —Cl, —Br, —I, —CO₂R, —C≡N, —NRR′, —SR, —SO₂R, —C(═O)R,        —OCF₃—CF₃, —CONRR′, —SO₂NRR′, —O—P(═O) (OR) (OR′), —N(R) (COR′),        —N(R) (SO₂R′), —(CH₂)₀₋₄—CO—-NR₇R′₇, —(CH₂)₀₋₄—CO— (C₁-C₁₂        alkyl), —(CH₂)₀₋₄—CO— (C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO— (C₂-C₁₂        alkynyl), —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R_(aryl),        —(CH₂)₀₋₄—R_(heteroaryl), —(CH₂)₀₋₄—R_(heterocyclyl),        —(CH₂)₀₋₄—CO—R_(aryl), (CH₂)₀₋₄—CO—R_(heteroaryl),        —(CH₂)₀₋₄—CO—R_(heterocyclyl), —(CH₂)₀₋₄—CO—R₁₁,        —(CH₂)₀₋₄—CO—O—R₁₁, —(CH₂)₀₋₄—SO₂—NR₇R′₇, —(CH₂)₀₋₄—SO—(C₁-C₈        alkyl), —(CH₂)₀₋₄—SO₂— (C₁-C₁₂ alkyl), —(CH₂)₀₋₄—SO₂— (C₃-C₇        cycloalkyl), —(CH₂)₀₋₄—N(H or R₁₁)—CO—O—R₁₁, —(CH₂)₀₋₄—N(H or        R₁₁)—CO—N(R₁₁)₂, —(CH₂)₀₋₄—N(H or R₁₁)—CS—N(R₁₁)₂,        —(CH₂)₀₋₄—N(—H or R₁₁)—CO—R₇, —(CH₂)₀₋₄—NR₇R″₇, —(CH₂)₀₋₄—R₁₀,        —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)— (O—R_(aryl))₂,        —(CH₂)₀₋₄—O—CO—N(R₁₁)₂, —(CH₂)₀₋₄—O—CS—N(R₁₁)₂,        —(CH₂)₀₋₄—O—(R₁₁), —(CH₂)₀₋₄—O—(R₁₁)—COOH, —(CH₂)₀₋₄—S—(R₁₁),        C₃-C₇ cycloalkyl, —(CH₂)₀₋₄—N(—H or R₁₁)—SO₂—R₇, or        —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, or    -   C₂-C₇ alkenyl or C₂-C₇ alkynyl, each of which is optionally        substituted with one, two or three groups independently selected        from halogen or —OH, or-   C₂-C₇ alkenyl or C₂-C₇ alkynyl, each of which is optionally    substituted with one, two or three groups independently selected    from halogen, C₁-C₃ alkyl, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,    amino, and mono- or dialkylamino, or-   —(CH₂)₀₋₄—O— (C₁-C₆ alkyl), where the alkyl portion is optionally    substituted with one, two, three, four, or five of halogen, or-   any two of R_(6a), R_(6b), R′_(6a), R″_(6b), R′″_(6a), R′″_(6b),    R′″_(6a) and R′″_(6b) together are oxo;-   R₇ and R₁₇ are the same or different and represent —H, —C₃-C₇    cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—    (C₁-C₃ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,    -   —C₁-C₆ alkyl chain with one double bond and one triple bond, or    -   —C₁-C₆ alkyl optionally substituted with —OH or —NH₂; or;    -   —C₁-C₆ alkyl optionally substituted with one, two or three        groups independently selected from halogen; or    -   heterocyclyl optionally substituted with halogen, amino, mono-        or dialkylamino, —OH, —C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl,        —SO₂—N(C₁-C₆ alkyl)₂, —SO₂— (C₁-C₄ alkyl), —CO—NH₂, —CO—NH—C₁-C₆        alkyl, oxo and —CO—N(C₁-C₆ alkyl)₂; or        -   C₁-C₆ alkyl optionally substituted with one, two or three            groups independently selected from C₁-C₃ alkyl, halogen,            —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or            dialkylamino; or        -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally            substituted with one, two or three groups independently            selected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or        -   C₁-C₆ alkoxy optionally substituted with one, two or three            of halogen;    -   aryl or heteroaryl, each of which is optionally substituted with        halogen, amino, mono- or dialkylamino, —OH, —C≡N, —SO₂—NH₂,        —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₄ alkyl),        —CO—NH₂, —CO—NH—C₁-C₆ alkyl, and —CO—N(C₁-C₆ alkyl)₂; or        -   C₁-C₆ alkyl optionally substituted with one, two or three            groups independently selected from C₁-C₃ alkyl, halogen,            —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or            dialkylamino; or        -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally            substituted with one, two or three groups independently            selected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,            C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or        -   C₁-C₆ alkoxy optionally substituted with one, two or three            of halogen;-   R₁₀ is heterocyclyl optionally substituted with one, two, three or    four groups independently selected from C₁-C₆ alkyl;-   R₁₁ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    —(CH₂)₀₋₂—R_(aryl), or —(CH₂)₀₋₂—R_(heteroaryl);-   R_(aryl) is aryl optionally substituted with halogen, amino, mono-    or dialkylamino, —OH, —C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl,    —SO₂—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₄ alkyl), —CO—NH₂, —CO—NH—C₁-C₆    alkyl, or —CO—N(C₁-C₆ alkyl)₂; or    -   C₁-C₆ alkyl optionally substituted with one, two or three groups        independently selected from C₁-C₃ alkyl, halogen, —OH, —SH,        —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or    -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally        substituted with one, two or three groups independently selected        from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        amino, and mono- or dialkylamino; or    -   C₁-C₆ alkoxy optionally substituted with one, two or three of        halogen;-   R_(heteroaryl) is heteroaryl, each of which is optionally    substituted with halogen, amino, mono- or dialkylamino, —OH, —C≡N,    —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆ alkyl)₂, —SO₂— (C₁-C₄    alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl, or —CO—N(C₁-C₆ alkyl)₂; or    -   C₁-C₆ alkyl optionally substituted with one, two or three groups        independently selected from C₁-C₃ alkyl, halogen, —OH, —SH,        —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or    -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally        substituted with one, two or three groups independently selected        from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        amino, and mono- or dialkylamino; or    -   C₁-C₆ alkoxy optionally substituted with one, two or three of        halogen;-   R_(heterocyclyl) is heterocyclyl optionally substituted with    halogen, amino, mono- or dialkylamino, —OH, —C≡N, —SO₂—NH₂,    —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₄ alkyl),    —CO—NH₂, —CO—NH—C₁-C₆ alkyl, ═O or —CO—N(C₁-C₆ alkyl)₂; or    -   C₁-C₆ alkyl optionally substituted with one, two or three groups        independently selected from C₁-C₃ alkyl, halogen, —OH, —SH,        —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or    -   C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally        substituted with one, two or three groups independently selected        from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,        amino, and mono- or dialkylamino; or    -   C₁-C₆ alkoxy optionally substituted with one, two or three of        halogen;-   R₂ is    -   —H; or —(CH₂)₀₋₄—R_(aryl) and —(CH₂)₀₋₄—R_(heteroaryl); or C₁-C₆        alkyl optionally substituted with one, two or three groups        independently selected from C₁-C₃ alkyl, halogen, —OH, —SH,        —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or    -   C₂-C₆ alkenyl, C₂-C₆ alkynyl or —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, each        of which is optionally substituted with one, two or three groups        independently selected from C₁-C₃ alkyl, halogen, —OH, —SH,        —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino;-   R₃ is —H, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —(CH₂)₀₋₄—R_(aryl), or    -   —(CH₂)₀₋₄—R_(heteroaryl); or    -   C₁-C₆ alkyl optionally substituted with one, two or three groups        independently selected from C₁-C₃ alkyl, halogen, —OH, —SH,        —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or    -   —(CH₂)₀₋₄—C₃-C₇ cycloalkyl optionally substituted with one, two        or three groups independently selected from C₁-C₃ alkyl,        halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or        dialkylamino; or-   R₂ and R₃ taken together with the carbon atom to which they are    attached form a carbocycle of three, four, five, six, or seven    carbon atoms, where one atom is optionally a heteroatom selected    from the group consisting of —O—, —S—, —SO₂—, and —NR₈—;-   R_(C) is hydrogen, —(CR₂₄₅R₂₅₀)₀₋₄-aryl, —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl, —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocyclyl, —(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocyclyl,    —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-heteroaryl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-heterocyclyl,    —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-aryl, —[C(R₂₅₅)    (R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂, —CH (aryl)₂, —CH(heteroaryl)₂,    —CH(heterocyclyl)₂, —CH(aryl)(heteroaryl),    —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)— (CH₂)₀₋₁-aryl,    —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₁-heteroaryl, —CH(-aryl or    -heteroaryl)-CO—O(C₁-C₄ alkyl), —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂,    (C₁-C₆ alkyl)-O— (C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,    —(CH₂)₀₋₆—C(═NR₂₃₅) (NR₂₃₅R₂₄₀), or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups        independently selected from the group consisting of R₂₀₅,        —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ (C₁-C₆ alkyl), —SH,        —NR₂₃₅C═ONR₂₃₅R₂₄₀, —C═ONR₂₃₅R₂₄₀, and —S(═O)₂NR₂₃₅R₂₄₀, or    -   —(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkyl is        optionally substituted with 1, 2, or 3 groups independently        selected from the group consisting of R₂₀₅, —CO₂H, and —CO₂—        (C₁-C₄ alkyl), or    -   cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl,        heteroaryl, or heterocyclyl wherein one, two or three carbons of        the cyclopentyl, cyclohexyl, or cycloheptyl is optionally        replaced with a heteroatom independently selected from NH,        NR₂₁₅, O, or S(═O)₀₋₂, and wherein the cyclopentyl, cyclohexyl,        or cycloheptyl group can be optionally substituted with one or        two groups that are independently R₂₀₅, ═O, —CO—NR₂₃₅R₂₄₀, or        —SO₂—(C₁-C₄ alkyl), or    -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl, each of which is optionally        substituted with 1, 2, or 3 R₂₀₅ groups, wherein    -   each aryl and heteroaryl is optionally substituted with 1, 2, or        3 R₂₀₀, and wherein each heterocyclyl is optionally substituted        with 1, 2, 3, or 4 R₂₁₀;-   R₂₀₀ at each occurrence is independently selected from —OH, —NO₂,    halogen, —CO₂H, C≡N, —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—CO— (C₁-C₁₂    alkyl), —(CH₂)₀₋₄—CO— (C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO— (C₂-C₁₂    alkynyl), —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—CO-aryl,    —(CH₂)₀₋₄—CO-heteroaryl, —(CH₂)₀₋₄—CO-heterocyclyl,    —(CH₂)₀₋₄—CO—O—R₂₁₅, —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—SO— (C₁-C₈    alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂ alkyl), —(CH₂)₀₋₄—SO₂— (C₃-C₇    cycloalkyl), —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—O—R₂₁₅, —(CH₂)₀₋₄—N(H or    R₂₁₅)—CO—N(R₂₁₅)₂, —(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂, —(CH₂)₀₋₄—N(—H or    R₂₁₅)—CO—R₂₂₀, —(CH₂)₀₋₄—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl),    —(CH₂)₀₋₄—O—P(O)— (OR₂₄₀)₂, —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂,    —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂, —(CH₂)₀₋₄—O— (R₂₁₅), —(CH₂)₀₋₄—O—    (R₂₁₅)—COOH, —(CH₂)₀₋₄—S— (R₂₁₅), —(CH₂)₀₋₄—O— (C₁-C₆ alkyl    optionally substituted with 1, 2, 3, or 5-F), C₃-C₇ cycloalkyl,    —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, or    -   C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups,        or    -   C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl, each of which is optionally        substituted with 1 or 2 R₂₀₅ groups, wherein    -   the aryl and heteroaryl groups at each occurrence are optionally        substituted with 1, 2, or 3 groups that are independently R₂₀₅,        R₂₁₀, or    -   C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are        independently R₂₀₅ or R₂₁₀, and wherein    -   the heterocyclyl group at each occurrence is optionally        substituted with 1, 2, or 3 groups that are independently R₂₁₀;-   R₂₀₅ at each occurrence is independently selected from C₁-C₆ alkyl,    halogen, —OH, —O-phenyl, —SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂,    NH(C₁-C₆ alkyl) or N—(C₁-C₆ alkyl) (C₁-C₆ alkyl);-   R₂₁₀ at each occurrence is independently selected from halogen,    C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, —NR₂₂₀R₂₂₅, OH, C≡N, —CO— (C₁-C₄    alkyl), —SO₂—NR₂₃₅R₂₄₀, —CO—NR₂₃₅R₂₄₀, —SO₂—(C₁-C₄ alkyl), ═O, or    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₇ cycloalkyl,        each of which is optionally substituted with 1, 2, or 3 R₂₀₅        groups;-   R₂₁₅ at each occurrence is independently selected from C₁-C₆ alkyl,    —(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,    and —(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocyclyl), wherein    -   the aryl group at each occurrence is optionally substituted with        1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀, and        wherein    -   the heterocyclyl and heteroaryl groups at each occurrence are        optionally substituted with 1, 2, or 3 R₂₁₀;-   R₂₂₀ and R₂₂₅ at each occurrence are independently selected from —H,    —C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆    alkyl)-O— (C₁-C₃ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆    alkyl chain with one double bond and one triple bond, -aryl,    -heteroaryl, and -heterocyclyl, or    -   —C₁-C₁₀ alkyl optionally substituted with —OH, —NH₂ or halogen,        wherein    -   the aryl, heterocyclyl and heteroaryl groups at each occurrence        are optionally substituted with 1, 2, or 3 R₂₇₀ groups-   R₂₃₅ and R₂₄₀ at each occurrence are independently H, or C₁-C₆    alkyl;-   R₂₄₅ and R₂₅₀ at each occurrence are independently selected from —H,    C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄ alkylheteroaryl, C₁-C₄    hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —(CH₂)₀₋₄—C₃-C₇    cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and phenyl; or-   R₂₄₅ and R₂₅₀ are taken together with the carbon to which they are    attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms,    where one carbon atom is optionally replaced by a heteroatom    selected from —O—, —S—, —SO₂—, and —NR₂₂₀—;-   R₂₅₅ and R₂₆₀ at each occurrence are independently selected from —H,    —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), —(C₁-C₄ alkyl)-aryl, —(C₁-C₄    alkyl)-heteroaryl, —(C₁-C₄ alkyl)-heterocyclyl, -aryl, -heteroaryl,    -heterocyclyl, —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-aryl,    —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl, —(CH₂)₁₋₄—R₂₆₅—    (CH₂)₀₋₄-heterocyclyl, or    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or —(CH₂)₀₋₄—C₃-C₇        cycloalkyl, each of which is optionally substituted with 1, 2,        or 3 R₂₀₅ groups, wherein    -   each aryl or phenyl is optionally substituted with 1, 2, or 3        groups that are independently R₂₀₅, R₂₁₀, or        -   C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are            independently R₂₀₅ or R₂₁₀, and wherein    -   each heterocyclyl is optionally substituted with 1, 2, 3, or 4        R₂₁₀;-   R₂₆₅ at each occurrence is independently —O—, —S— or —N(C₁-C₆    alkyl)-;-   R₂₇₀ at each occurrence is independently R₂₀₅, halogen C₁-C₆ alkoxy,    C₁-C₆ haloalkoxy, NR₂₃₅R₂₄₀, —OH, —C≡N, —CO— (C₁-C₄ alkyl),    —SO₂—NR₂₃₅R₂₄₀, —CO—NR₂₃₅R₂₄₀, —SO₂— (C₁-C₄ alkyl), ═O, or    -   C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or —(CH₂)₀₋₄—C₃-C₇        cycloalkyl, each of which is optionally substituted with 1, 2,        or 3 R₂₀₅ groups;        and pharmaceutically acceptable salts thereof.

The invention also provides intermediates and methods useful forpreparing the compounds of formula X.

The invention further provides pharmaceutical compositions comprising acompound of formula X.

The present invention also provides the use of a compound of formula (X)and pharmaceutically acceptable salts thereof for the manufacture of amedicament. The present invention also provides a method of treating apatient who has Alzheimer's Disease or other diseases that can betreated by inhibiting beta-secretase activity.

DETAILED DESCRIPTION OF THE INVENTION

The compounds encompassed by the instant invention are those describedby the general formula (I) set forth above, and the pharmaceuticallyacceptable salts and prodrugs thereof.

In an embodiment, the compounds of formula (I) have syn stereochemistry.

In an embodiment, the compounds of formula (I) have antistereochemistry.

The invention also provides intermediates and methods useful forpreparing the compounds of formula I.

In an embodiment, the compound has formula (Ia):

where m, R₁, R₂, R₃, R₄, R′₄, R″₄, R′″₄ and R_(c), are as defined abovefor (I) and D, E and G independently represent N, N⁺—O⁻ or CR₆ where R₆is as defined above for (I), provided that not more than two of D, E andG are N and not more than one of D, E and G is N⁺—O⁻. The aromatic ringcontaining D, E and G can also be optionally substituted with up to fourgroups selected from R₆, R₁₆, R″₆ and R′″₆, as defined above for (I).Preferred compounds for formula (Ia) are those where D, E and G are CR₆;R₂ and R₃ are hydrogen; R₁ is —C₁-C₃ alkyl-aryl, the aryl optionallysubstituted with one or two groups independently selected from halogen;and R₁ is —C₁-C₃ alkyl-aryl, the aryl optionally substituted withhalogen or —C₁-C₆ alkyl. More preferred compounds of formula (Ia) arethose where m is 0; R₄ and R₁₄ are hydrogen; R₁ is phenylmethyl, wherethe phenyl is optionally substituted with one or two groupsindependently selected from halogen; R₂ and R₃ are hydrogen; and R_(c)is phenylmethyl, where the phenyl is optionally substituted with halogenor —C₁-C₆ alkyl.

In another embodiment, the compound has a formula of (Ib):

where m, R₁, R₂, R₃, R₄, R′₄, R″₄, R′″₄ and R_(c) are as defined abovefor (I) and Ar is an aromatic ringed system other than the aromatic ringcontaining D, E and G of formula (Ia) above, and is optionallysubstituted with one, two, three or four groups independently selectedfrom R₆, R′₆, R″₆ and R′″₆, as defined above for (I); where Ar isselected from 1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl,1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl,1,2,3,4-tetrahydronaphthalen-1-yl, 2,3-dihydro-1H-inden-1-yl,2,3-dihydro-1-benzofuran-5-yl, benzofuran-4-yl,2,3-dihydro-1H-inden-5-yl, 6-oxopyridazin-1(6H)-yl, 1-naphthyl,2-naphthyl, 3,4-dihydronaphthalen-1-yl, 1H-indol-1-yl,2,3-dihydro-1-benzofuran-4-yl, 1H-pyrazol-1-yl,2-oxo-1,3-benzoxazol-3(2H)-yl, 1H-benzimidazol-2-yl,2-thioxo-1,3-benzothiazol-3(2H)-yl, 1,2,4-oxadiazol-5-yl,1H-benzimidazol-1-yl, [1,2,4]triazolo[4,3-a]pyrimidin-3-yl,2H-tetraazol-2-yl, 1,3-benzothiazol-2-yl,2-oxo-2,3-dihydro-1H-benzimidazol-1-yl, 2,3-dihydro-1H-indol-1-yl,1H-tetraazol-1-yl, 1H-1,2,3-benzotriazol-1-yl, 1,3-benzodioxol-5-yl,thien-2-yl, thien-3-yl, 2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl,1H-indol-3-yl, benzothien-4-yl,2,6-dioxo-1,2,3,6-tetrahydro-9H-purin-9-yl,2-oxo-1,3-benzothiazol-3(2H)-yl, 1,3-thiazol-5-yl, 1,3-benzoxazol-5-yl,2H-1,2,3-benzotriazol-2-yl, 1,3-thiazol-4-yl, 1H-1,2,4-triazol-1-yl,1H-imidazol-1-yl, 2-furyl, 4H-[1,2,4]triazolo[1,5-a]benzimidazol-4-yl,1H-indol-2-yl, 3,4-dihydro-2H-1,5-benzodioxepin-7-yl,2-oxo-pyridin-1(2H)-yl, 1-benzofuran-2-yl, dibenzo[b,d]furan-2-yl,6-oxo-pyridazin-1(6H)-yl, 3,4-dihydro-2H-chromen-6-yl,3-oxo-2,3-dihydro-1H-isoindol-1-yl, 1H-pyrrol-1-yl,1-oxo-1,3-dihydro-2H-isoindol-2-yl,2-thioxo-2,3-dihydro-1,3-thiazol-4-yl, isoxazol-5-yl,2,3-dihydro-1,4-benzodioxin-6-yl, 2-oxo-2H-1,3-benzoxazin-3(4H)-yl,2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl,2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 1H-pyrrol-2-yl,[1,2,4]triazolo[1,5-a]pyrimidin-2-yl, 4H-1,2,4-triazol-3-yl,2,4-dioxo-1,2,3,4-tetrahydropyridin-3-yl and3-oxo-2,1-benzisothiazol-1(3H)-yl. Preferred compounds of formula (Ib)are those where R₂ and R₃ are hydrogen; R₁ is —C₁-C₃ alkyl-aryl, thearyl optionally substituted with one or two groups independentlyselected from halogen; and R_(c) is hydroxy C₁-C₆ alkyl, —C₁-C₃alkyl-aryl, the aryl optionally substituted with halogen or —C₁-C₆alkyl. More preferred compounds of formula (Ib) are those where m is 0;R₄ and R₁₄ are hydrogen; R₁ is phenylmethyl, where the phenyl isoptionally substituted with one or two groups independently selectedfrom halogen; R₂ and R₃ are hydrogen; and R_(c) is phenylmethyl, wherethe phenyl is optionally substituted with halogen or —C₁-C₆ alkyl.

In an embodiment, the compound has formula (Ic):

where m, R₁, R₂, R₃, R₄, R′₄, R″₄, R′″₄ and R_(c), are as defined abovefor (I) and B₁ is selected from piperazin-1-yl, piperidine-4-yl,morpholin-4-yl, 4,5,6,7,3a,7a-hexahydroisoindol-2-yl,3-azabicyclo[3.2.2]nonan-3-yl, 1,4-diazaperhydroepin-1-yl,1,4-thiazaperhydroin-1-yl, thiolan-3-yl, thiolan-2-yl andimidazolidin-1-yl, each of which is optionally substituted with up toeight groups selected from R₆, R_(6a), R′₆, R_(6a), R″₆, R″_(6a), R′″₆and R′″_(6a). Preferred compounds of formula (Ic) are those where B₁ ispiperazin-1-yl or piperidine-4-yl, each of which is optionallysubstituted with one, two or three groups selected from oxo and C₁-C₆alkyl; R₂ and R₃ are hydrogen; R₁ is —C₁-C₃ alkyl-aryl, the aryloptionally substituted with one or two groups independently selectedfrom halogen; and R_(c) is —C₁-C₃ alkyl-aryl, the aryl optionallysubstituted with halogen or —C₁-C₆ alkyl. More preferred compounds offormula (Ic) are those where m is 0; R₄ and R₁₄ are hydrogen; B₁ ispiperazin-1-yl or piperidine-4-yl, each of which is optionallysubstituted with one, two or three groups selected from oxo and C₁-C₆alkyl; R₁ is phenylmethyl, where the phenyl is optionally substitutedwith one or two groups independently selected from halogen; R₂ and R₃are hydrogen; and R_(c) is phenylmethyl, where the phenyl is optionallysubstituted with halogen or —C₁-C₆ alkyl.

In another embodiment, the compound has a formula of (Id):

where m, R₁, R₂, R₃, R₄, R′₄, R″₄, R′″₄ and R_(c), are as defined abovefor (I) and B₂ is cycloalkyl optionally substituted with up to eightgroups selected from R₆, R_(6a), R′₆, R′_(6a), R″₆, R″_(6a), R′″₆ andR′″_(6a). Preferred compounds of formula (Id) are those where B₂ iscyclohexyl optionally substituted with one, two or three groups selectedfrom oxo and C₁-C₆ alkyl; R₂ and R₃ are hydrogen; R₁ is —C₁-C₃alkyl-aryl, the aryl optionally substituted with one or two groupsindependently selected from halogen; and R₁ is —C₁-C₃ alkyl-aryl, thearyl optionally substituted with halogen or —C₁-C₆ alkyl. More preferredcompounds of formula (Id) are those where m is 0; R₄ and R₁₄ arehydrogen; B₂ is cyclohexyl optionally substituted with oxo and C₁-C₆alkyl; R₁ is phenylmethyl, where the phenyl is optionally substitutedwith one or two groups independently selected from halogen; R₂ and R₃are hydrogen; and R_(c) is phenylmethyl, where the phenyl is optionallysubstituted with halogen or —C₁-C₆ alkyl.

The present invention also includes a method of treating a patient whohas, or in preventing a patient from getting, a disease or conditionselected from the group consisting of Alzheimer's disease, for helpingprevent or delay the onset of Alzheimer's disease, for treating patientswith mild cognitive impairment (MCI) and preventing or delaying theonset of Alzheimer's disease in those who would progress from MCI to AD,for treating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating Frontotemporaldementias with Parkinsonism (FTDP), for treating other degenerativedementias, including dementias of mixed vascular and degenerativeorigin, dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, or diffuse Lewy body type of Alzheimer'sdisease and who is in need of such treatment which includesadministration of a therapeutically effective amount of a compound offormula (I) and pharmaceutically acceptable salts thereof.

In an embodiment, this method of treatment can be used where the diseaseis Alzheimer's disease.

In an embodiment, this method of treatment can help prevent or delay theonset of Alzheimer's disease.

In an embodiment, this method of treatment can be used where the diseaseis mild cognitive impairment.

In an embodiment, this method of treatment can be used where the diseaseis Down's syndrome.

In an embodiment, this method of treatment can be used where the diseaseis Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.

In an embodiment, this method of treatment can be used where the diseaseis cerebral amyloid angiopathy.

In an embodiment, this method of treatment can be used where the diseaseis FTDP.

In an embodiment, this method of treatment can be used where the diseaseis degenerative dementias.

In an embodiment, this method of treatment can be used where the diseaseis diffuse Lewy body type of Alzheimer's disease.

In an embodiment, this method of treatment can treat an existingdisease.

In an embodiment, this method of treatment can prevent a disease fromdeveloping.

In an embodiment, this method of treatment can employ therapeuticallyeffective amounts: for oral administration from about 0.1 mg/day toabout 1,000 mg/day; for parenteral, sublingual, intranasal, intrathecaladministration from about 0.5 to about 100 mg/day; for depoadministration and implants from about 0.5 mg/day to about 50 mg/day;for topical administration from about 0.5 mg/day to about 200 mg/day;for rectal administration from about 0.5 mg to about 500 mg.

In an embodiment, this method of treatment can employ therapeuticallyeffective amounts: for oral administration from about 1 mg/day to about100 mg/day; and for parenteral administration from about 5 to about 50mg daily.

In an embodiment, this method of treatment can employ therapeuticallyeffective amounts for oral administration from about 5 mg/day to about50 mg/day.

The present invention also includes a pharmaceutical composition whichincludes a substituted amine of formula (I) and pharmaceuticallyacceptable salts thereof.

The present invention also includes the use of a substituted amine offormula (I) and pharmaceutically acceptable salts thereof for themanufacture of a medicament for use in treating a patient who has, or inpreventing a patient from getting, a disease or condition selected fromthe group consisting of Alzheimer's disease, for helping prevent ordelay the onset of Alzheimer's disease, for treating patients with mildcognitive impairment (MCI) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobar hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse Lewy body type ofAlzheimer's disease and who is in need of such treatment.

In an embodiment, this use of a substituted amine of formula (I) can beemployed where the disease is Alzheimer's disease.

In an embodiment, this use of a substituted amine of formula (I) canhelp prevent or delay the onset of Alzheimer's disease.

In an embodiment, this use of a substituted amine of formula (I) can beemployed where the disease is mild cognitive impairment.

In an embodiment, this use of a substituted amine of formula (I) can beemployed where the disease is Down's syndrome.

In an embodiment, this use of a substituted amine of formula (I) can beemployed where the disease is Hereditary Cerebral Hemorrhage withAmyloidosis of the Dutch-Type.

In an embodiment, this use of a substituted amine of formula (I) can beemployed where the disease is cerebral amyloid angiopathy.

In an embodiment, this use of a substituted amine of formula (I) can beemployed where the disease is degenerative dementias.

In an embodiment, this use of a substituted amine of formula (I) can beemployed where the disease is diffuse Lewy body type of Alzheimer'sdisease.

In an embodiment, this use of a substituted amine employs apharmaceutically acceptable salt selected from the group consisting ofsalts of the following acids hydrochloric, hydrobromic, hydroiodic,nitric, sulfuric, phosphoric, citric, TFA, methanesulfonic,CH₃—(CH₂)—COOH where n is 0 thru 4, HOOC—(CH₂)_(n)—COOH where n is asdefined above, HOOC—CH═CH—COOH, and phenyl-COOH.

The present invention also includes methods for inhibitingbeta-secretase activity, for inhibiting cleavage of amyloid precursorprotein (APP), in a reaction mixture, at a site between Met596 andAsp597, numbered for the APP-695 amino acid isotype, or at acorresponding site of an isotype or mutant thereof; for inhibitingproduction of amyloid beta peptide (A beta) in a cell; for inhibitingthe production of beta-amyloid plaque in an animal; and for treating orpreventing a disease characterized by beta-amyloid deposits in the brainwhich include administration of a therapeutically effective amount of asubstituted amine of formula (I) and pharmaceutically acceptable saltsthereof.

The present invention also includes a method for inhibitingbeta-secretase activity, including exposing said beta-secretase to aneffective inhibitory amount of a compound of the formula (I) or apharmaceutically acceptable salt thereof.

Preferably, this method employs a compound that inhibits 50% of theenzyme's activity at a concentration of less than 50 micromolar.

This method more preferably employs a compound that inhibits 50% of theenzyme's activity at a concentration of 10 micromolar or less

This method even more preferably employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of 1 micromolar or less.

In a particular embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 nanomolar or less.

In an embodiment, this method includes exposing said beta-secretase tosaid compound in vitro.

In an embodiment, this method includes exposing said beta-secretase tosaid compound in a cell.

In an embodiment, this method includes exposing said beta-secretase tosaid compound in a cell in an animal.

In an embodiment, this method includes exposing said beta-secretase tosaid compound in a human.

The present invention also includes a method for inhibiting cleavage ofamyloid precursor protein (APP), in a reaction mixture, at a sitebetween Met596 and Asp597, numbered for the APP-695 amino acid isotype;or at a corresponding site of an isotype or mutant thereof, includingexposing said reaction mixture to an effective inhibitory amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

In an embodiment, this method employs a cleavage site: between Met652and Asp653, numbered for the APP-751 isotype; between Met 671 and Asp672, numbered for the APP-770 isotype; between Leu596 and Asp597 of theAPP-695 Swedish Mutation; between Leu652 and Asp653 of the APP-751Swedish Mutation; or between Leu671 and Asp672 of the APP-770 SwedishMutation.

In an embodiment, this method exposes said reaction mixture in vitro.

In an embodiment, this method exposes said reaction mixture in a cell.

In an embodiment, this method exposes said reaction mixture in an animalcell.

In an embodiment, this method exposes said reaction mixture in a humancell.

The present invention also includes a method for inhibiting productionof amyloid beta peptide (A beta) in a cell, including administering tosaid cell an effective inhibitory amount of a compound of formula (I) ora pharmaceutically acceptable salt thereof.

In an embodiment, this method includes administering to an animal.

In an embodiment, this method includes administering to a human.

The present invention also includes a method for inhibiting theproduction of beta-amyloid plaque in an animal, including administeringto said animal an effective inhibitory amount of a compound of theformula (I) or a pharmaceutically acceptable salt thereof.

In an embodiment, this method includes administering to a human.

The present invention also includes a method for treating or preventinga disease characterized by beta-amyloid deposits in the brain includingadministering to a patient an effective therapeutic amount of ahydroxyethylene compound of the formula (I) or a pharmaceuticallyacceptable salt thereof.

Preferably, this method employs a compound that inhibits 50% of theenzyme's activity at a concentration of less than 50 micromolar.

This method more preferably employs a compound that inhibits 50% of theenzyme's activity at a concentration of 10 micromolar or less

This method even more preferably employs a compound that inhibits 50% ofthe enzyme's activity at a concentration of 1 micromolar or less.

In a particular embodiment, this method employs a compound that inhibits50% of the enzyme's activity at a concentration of 10 nanomolar or less.

In an embodiment, this method employs a compound at a therapeutic amountin the range of from about 0.1 to about 1000 mg/day.

In an embodiment, this method employs a compound at a therapeutic amountin the range of from about 15 to about 1500 mg/day.

In an embodiment, this method employs a compound at a therapeutic amountin the range of from about 1 to about 100 mg/day.

In an embodiment, this method employs a compound at a therapeutic amountin the range of from about 5 to about 50 mg/day.

In an embodiment, this method can be used where said disease isAlzheimer's disease.

In an embodiment, this method can be used where said disease is MildCognitive Impairment, Down's Syndrome, or Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch Type.

The present invention also includes a composition includingbeta-secretase complexed with a compound of formula (I) or apharmaceutically acceptable salt thereof.

The present invention also includes a method for producing abeta-secretase complex including exposing beta-secretase to a compoundof formula (I) or a pharmaceutically acceptable salt thereof, in areaction mixture under conditions suitable for the production of saidcomplex.

In an embodiment, this method employs exposing in vitro.

In an embodiment, this method employs a reaction mixture that is a cell.

The present invention also includes a component kit including componentparts capable of being assembled, in which at least one component partincludes a compound of formula Xa enclosed in a container.

In an embodiment, this component kit includes lyophilized compound, andat least one further component part includes a diluent.

The present invention also includes a container kit including aplurality of containers, each container including one or more unit doseof a compound of formula (I) or a pharmaceutically acceptable saltthereof.

In an embodiment, this container kit includes each container adapted fororal delivery and includes a tablet, gel, or capsule.

In an embodiment, this container kit includes each container adapted forparenteral delivery and includes a depot product, syringe, ampoule, orvial.

In an embodiment, this container kit includes each container adapted fortopical delivery and includes a patch, medipad, ointment, or cream.

The present invention also includes an agent kit including a compound offormula (I) or a pharmaceutically acceptable salt thereof; and one ormore therapeutic agent selected from the group consisting of anantioxidant, an anti-inflammatory, a gamma secretase inhibitor, aneurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an Abeta peptide, and an anti-A beta antibody.

The present invention also includes a composition including a compoundof formula (I) or a pharmaceutically acceptable salt thereof; and aninert diluent or edible carrier.

In an embodiment, this composition includes a carrier that is an oil.

The present invention also includes a composition including a compoundof formula (I) or a pharmaceutically acceptable salt thereof; and abinder, excipient, disintegrating agent, lubricant, or gildant.

The present invention also includes a composition including a compoundof formula (I) or a pharmaceutically acceptable salt thereof; disposedin a cream, ointment, or patch.

The present invention provides compounds, compositions, kits, andmethods for inhibiting beta-secretase-mediated cleavage of amyloidprecursor protein (APP). More particularly, the compounds, compositions,and methods of the invention are effective to inhibit the production ofA beta peptide and to treat or prevent any human or veterinary diseaseor condition associated with a pathological form of A beta peptide.

The compounds, compositions, and methods of the invention are useful fortreating humans who have Alzheimer's Disease (AD), for helping preventor delay the onset of AD, for treating patients with mild cognitiveimpairment (MCI), and preventing or delaying the onset of AD in thosepatients who would otherwise be expected to progress from MCI to AD, fortreating Down's syndrome, for treating Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch Type, for treating cerebral beta-amyloidangiopathy and preventing its potential consequences such as single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, fortreating dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, and diffuse Lewy body type AD.

The compounds of the invention possess beta-secretase inhibitoryactivity. The inhibitory activities of the compounds of the inventionare readily demonstrated, for example, using one or more of the assaysdescribed herein or known in the art.

By “Protecting Group” in the present invention is meant any suitableorganic protecting group such as disclosed in T. W. Green and P. G. M.Wuts in “Protective Groups in Organic Chemistry, John Wiley and Sons,1991. Preferred protecting groups in the present invention aret-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido,trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl,4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluoyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluoylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobrornyloxycarbonyl, 1-piperidyloxycarbonyl, 9-fluoroenylmethylcarbonate, —CH—CH═CH₂, or phenyl-C(═N—)—H.

By “alkyl” and “C₁-C₆ alkyl” in the present invention is meant straightor branched chain alkyl groups having 1-6 carbon atoms, such as, methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl. It is understood that in cases where an alkyl chain of asubstituent (e.g. of an alkyl, alkoxy or alkenyl group) is shorter orlonger than 6 carbons, it will be so indicated in the second “C” as, forexample, “C₁-C₁₀” indicates a maximum of 10 carbons.

By “alkoxy” and “C₁-C₆ alkoxy” in the present invention is meantstraight or branched chain alkyl groups having 1-6 carbon atoms,attached through at least one divalent oxygen atom, such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and3-methylpentoxy.

By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

“Alkenyl” and “C₂-C₆ alkenyl” means straight and branched hydrocarbonradicals having from 2 to 6 carbon atoms and from one to three doublebonds and includes, for example, ethenyl, propenyl, 1-but-3-enyl,1-pent-3-enyl, 1-hex-5-enyl and the like.

“Alkynyl” and “C₂-C₆ alkynyl” means straight and branched hydrocarbonradicals having from 2 to 6 carbon atoms and one or two triple bonds andincludes ethynyl, propynyl, butynyl, pentyn-2-yl and the like.

As used herein, the term “cycloalkyl” refers to saturated carbocyclicradicals having three to twelve carbon atoms. The cycloalkyl can bemonocyclic, or a polycyclic fused system, and can optionally contain adouble bond. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl groups hereinare unsubstituted or, as specified, substituted in one or moresubstitutable positions with various groups. For example, suchcycloalkyl groups may be optionally substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C₁-C₆) alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

By “aryl” is meant an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensedrings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-, di-,or trisubstituted. Preferred aryl groups of the present invention arephenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl,tetralinyl or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The arylgroups herein are unsubstituted or, as specified, substituted in one ormore substitutable positions with various groups. For example, such arylgroups may be optionally substituted with, for example, C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆) alkyl, mono (C₁-C₆)alkylamino(C₁-C₆) alkyl, di(C₁-C₆)alkylamino(C₁-C₆)alkyl, —COOH,—C(═O)O(C₁-C₆ alkyl), —C(═O)NH₂, —C(═O)N(mono- or di-C₁-C₆ alkyl),—S(C₁-C₆ alkyl), —SO₂ (C₁-C₆ alkyl), —O—C(═O) (C₁-C₆ alkyl), —NH—C(═O)—(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)-C(═O)—(C₁-C₆ alkyl), —NH—SO₂— (C₁-C₆alkyl), —N(C₁-C₆ alkyl)-SO₂— (C₁-C₆ alkyl), —NH—C(═O)NH₂,—NH—C(═O)N(mono- or di-C₁-C₆ alkyl), —NH(C₁-C₆ alkyl)-C(═O)—NH₂ or—NH(C₁-C₆ alkyl)-C(═O)—N-(mono- or di-C₁-C₆ alkyl).

By “heteroaryl” is meant one or more aromatic ring systems of 5-, 6-, or7-membered rings which includes fused ring systems of 9-11 atomscontaining at least one and up to four heteroatoms selected fromnitrogen, oxygen, or sulfur. Preferred heteroaryl groups of the presentinvention include pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl,isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl,isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl,benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl,phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl,isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide,tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinylN-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolylN-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide,benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide,thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. The heteroarylgroups herein are unsubstituted or, as specified, substituted in one ormore substitutable positions with various groups. For example, suchheteroaryl groups may be optionally substituted with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono(C₁-C₆)alkylamino(C₁-C₆)alkyl ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl, —COOH, —C(═O)O(C₁-C₆ alkyl), —C(═O)NH₂,—C(═O)N(mono- or di-C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —SO₂ (C₁-C₆ alkyl),—O—C(═O) (C₁-C₆ alkyl), —NH—C(═O)— (C₁-C₆ alkyl), —N(C₁-C₆ alkyl)-C(═O)—(C₁-C₆ alkyl), —NH—SO₂— (C₁-C₆ alkyl), —N(C₁-C₆ alkyl)-SO₂— (C₁-C₆alkyl), —NH—C(═O)NH₂, —NH—C(═O)N(mono- or di-C₁-C₆ alkyl), —NH(C₁-C₆alkyl)-C(═O)—NH₂ or —NH(C₁-C₆ alkyl)-C(═O)—N-(mono- or di-C₁-C₆ alkyl).

By “heterocycle”, “heterocycloalkyl” or “heterocyclyl” is meant one ormore carbocyclic ring systems of 4-, 5-, 6-, or 7-membered rings whichincludes fused ring systems of 9-11 atoms containing at least one and upto four heteroatoms selected from nitrogen, oxygen, or sulfur. Theheterocycle may optionally contain a double bond. Preferred heterocyclesof the present invention include morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide andhomothiomorpholinyl S-oxide. The heterocycle groups herein areunsubstituted or, as specified, substituted in one or more substitutablepositions with various groups. For example, such heterocycle groups maybe optionally substituted with C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,hydroxy, cyano, nitro, amino, mono(C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono (C₁-C₆)alkylamino(C₁-C₆)alkyl,di(C₁-C₆)alkylamino(C₁-C₆)alkyl or ═O.

Synthesis

The present invention is the substituted amines (I), which are useful intreating and preventing Alzheimer's disease. The anti-Alzheimer'ssubstituted amines (I) are made by methods well known to those skilledin the art from starting compounds known to those skilled in the art.The process chemistry is well known to those skilled in the art. Themost general process to prepare the compounds of formulas (I), (Ia) and(Ib) of the present invention is set forth in CHART A below, where m, B,R₁, R₂, R₃, R₄, R₁₄, R″₄, R′″₄, R₆, R′₆, R″₆, R′″₆ and R_(c) are asdefined above for (I). X₂ and X₃ are functional organic groups definedin more detail below.

The chemistry is straight forward and in summary involves the steps ofN-protecting an amino acid (1) starting material to produce thecorresponding protected amino acid (II), reaction of the protected aminoacid (II) with diazomethane followed by work-up to add a carbon atom toproduce the corresponding protected compound (III), reduction of theprotected compound (III) to the corresponding alcohol (IV), formation ofthe corresponding epoxide (V), opening of the epoxide (V) with aC-terminal amine, R_(C)—NH₂ (VI) to produce the corresponding protectedalcohol (VII) which then has the nitrogen protecting group removed toproduce the corresponding amine (VIII), which is then reacted with anamide forming agent of the formula (IX) to produce the anti-Alzheimercompounds of formula (I). One skilled in the art will appreciate thatthese are all well known reactions in organic chemistry. A chemistskilled in the art, knowing the chemical structure of the biologicallyactive compounds of formula (I) of the invention would be able toprepare them by known methods from known starting materials without anyadditional information. The explanation below therefore is not necessarybut is deemed helpful to those skilled in the art who desire to make thecompounds of the present invention.

The backbone of the compounds of the present invention is ahydroxyethylamine moiety, —NH—CH(R)—CH(OH)—. It can be readily preparedby methods disclosed in the literature and known to those skilled in theart. For example, J. Med. Chem., 36, 288-291 (1992), TetrahedronLetters, 28, 5569-5572 (1987), J. Med. Chem., 38, 581-584 (1994) andTetrahedron Letters, 38, 619-620 (1997) all disclose processes toprepare hydroxyethylamine type compounds.

CHART A sets forth a general method used in the present invention toprepare the compounds of formula (I). The anti-Alzheimer compounds offormula (I) can be prepared by starting with the corresponding aminoacid (1). The amino acids (1) are well known to those skilled in the artor can be readily prepared from known compounds by methods well known tothose skilled in the art. The compounds of formula (I) have at least twoenantiomeric centers which give four enantiomers. The first of theseenantiomeric centers derives from the amino acid starting material (1).It is preferred to commercially obtain or produce the desired enantiomer(S) rather than produce an enantiomerically impure mixture and then haveto separate out the desired enantiomer (S). It is preferred to start theprocess with enantiomerically pure (S)-amino acid (1) of the sameconfiguration as that of the compounds of formula (I). For the aminoacids (1), R₁ is as defined above for formula (I).

It is preferred that R₁ be —(CH₂)₀₋₁-aryl or —(CH₂)₀₋₁-heteroaryl. It ismore preferred that R₁ is —(CH₂)-aryl or —(CH₂)₀₋₁-heteroaryl. It isfurther preferred that aryl is phenyl; it is even more preferred thatthe phenyl is substituted with two —F. It is additionally preferred thatthe —F substitution is 3,5-difluorobenzyl.

When R₁ is heteroaryl or heterocyclyl, the bond from the heteroaryl orheterocyclyl group to the —(CH₂)— group can be from any ring atom whichhas an available valence provided that such bond does not result information of a charged species or unstable valence. This means that theheteroaryl or heterocyclyl group is bonded to —(CH₂)— by any ring atomof the parent heteroaryl or heterocyclyl group which is substituted byhydrogen such that the new bond to the heteroaryl or heterocyclyl groupreplaces the hydrogen atom and its bond.

The first step of the process is to protect the free amino group of the(S)-amino acid (1) with an amino protecting group to produce the(S)-protected amino acid (II) by methods well known to those skilled inthe art. Amino protecting groups are well known to those skilled in theart. See for example, “Protecting Groups in Organic Synthesis”, JohnWiley and sons, New York, N.Y., 1981, Chapter 7; “Protecting Groups inOrganic Chemistry”, Plenum Press, New York, N.Y., 1973, Chapter 2. Thefunction of the amino protecting group is to protect the free aminofunctionality (—NH₂) during subsequent reactions on the (S)-amino acid(1) which would not proceed well, either because the amino group wouldreact and be functionalized in a way that is inconsistent with its needto be free for subsequent reactions, or the free amino group wouldinterfere in the reaction. When the amino protecting group is no longerneeded, it is removed by methods well known to those skilled in the art.By definition the amino protecting group must be readily removable as isknown to those skilled in the art by methods well known to those skilledin the art.

The (S)-protected amino acid (II) is transformed to the corresponding(S)-protected compound (III) by two different methods depending on thenature of R₂ and R₃. R₂ and R₃ are as defined above for formula (I).

It is preferred that R₂ and R₃ both be —H. If R₂ and R₃ are not thesame, an additional enantiomeric center is added to the molecule. If itis desired that both R₂ and R₃ are —H, then the (S)-protected amino acid(II) is reacted with diazomethane, as is well known to those skilled inthe art, followed by reaction with a compound of the formula H—X₁ toproduce the (S)-protected compound (III). X₁ includes —Cl, —Br, —I,—O-tosylate, —O-mesylate, —O-nosylate; it is preferred that —X₁ be —Bror —Cl. Suitable reaction conditions include running the reaction ininert solvents, such as but not limited to ether, tetrahydrofuran andthe like. The reactions from the (S)-protected amino acid (II) to the(S)-protected compound (III) are carried out for a period of timebetween 10 minutes and 1 day and at temperatures ranging from −78degrees to 20-25 degrees C. It is preferred to conduct the reactions fora period of time between 1-4 hours and at temperatures between −30degrees to −10 degrees C. This process adds one methylene group.

Alternatively, the (S)-protected compounds of formula (III) can beprepared by first converting the (S)-protected amino acid (II) to acorresponding methyl or ethyl ester, according to methods wellestablished in the art, followed by treatment with a reagent of formulaX₁—C(R₂) (R₃)—X₁ and a strong metal base. The base serves to affect ahalogen-metal exchange, where the —X₁ undergoing exchange is a halogenselected from chlorine, bromine or iodine. The nucleophilic addition tothe ester derivative gives directly the (S)-protected compound (III).Suitable bases include, but are not limited to the alkyllithiumsincluding, for example, sec-butyllithium, n-butyllithium, andt-butyllithium. The reactions are preferably conducted at lowtemperature, such as −78 degrees C. Suitable reaction conditions includerunning the reaction in inert solvents, such as but not limited to,ether, tetrahydrofuran, and the like. Where R₂ and R₃ are both hydrogen,then examples of X₁—C(R₂) (R₃)—X₁ include dibromomethane, diiodomethane,chloroiodo-methane, bromoiodomethane, and bromochloromethane. Oneskilled in the art knows suitable and preferred conditions for toconducting this reaction. Furthermore, if R₂ and/or R₃ are not —H, thenby the addition of —C(R₂) (R₃)—X₁ to esters of the (S)-protected aminoacid (II) to produce the (S)-protected compound (III), an additionalchiral center will be incorporated into the product, provided that R₂and R₃ are not the same.

The (S)-protected compound (III) is then reduced by methods well knownto those skilled in the art for reduction of a ketone to thecorresponding secondary alcohol affording the corresponding alcohol(IV). The methods and reaction conditions for reducing the (S)-protectedcompound (III) to the corresponding alcohol (IV) include, for example,sodium borohydride, lithium borohydride, borane, diisobutylaluminumhydride, and lithium aluminium hydride. Sodium borohydride is thepreferred reducing agent. The reductions are carried out for a period oftime between 1 hour and 3 days at temperatures ranging from −78 degreesC. to elevated temperature up to the reflux point of the solventemployed. It is preferred to conduct the reduction between −78 degreesC. and 0 degrees C. If borane is used, it may be employed as a complex,for example, borane-methyl sulfide complex, borane-piperidine complex,or borane-tetrahydrofuran complex. Suitable and preferred combinationsof reducing agents and reaction conditions are known to those skilled inthe art; see for example, Larock, R. C. in Comprehensive OrganicTransformations, VCH Publishers, 1989. The reduction of the(S)-protected compound (III) to the corresponding alcohol (IV) producesthe second chiral center (third chiral center if R₂ and R₃ are not thesame). The reduction of the (S)-protected compound (III) produces amixture of enantiomers at the second center, (S, R/S)-alcohol (IV). Thisenantiomeric mixture is then separated by methods known to those skilledin the art such as selective low-temperature recrystallization orchromatographic separation, for example by HPLC, employing commerciallyavailable chiral columns. The enantiomer that is used in the remainderof the process of CHART A is the (S,S)-alcohol (IV) since thisenantiomer will give the desired biologically active anti-Alzheimer(S,R)-compounds of formula (I).

The (S,S)-alcohol (IV) is transformed to the corresponding epoxide (V)by methods known to those skilled in the art. The stereochemistry of the(S)-(IV) center is maintained in forming the epoxide (V). A preferredmethod is by reaction with base, for example, but not limited to,hydroxide ion generated from sodium hydroxide, potassium hydroxide,lithium hydroxide and the like. Reaction conditions include the use ofC₁-C₆ alcohol solvents; ethanol is preferred. A common co-solvent, suchas for example, ethyl acetate may also be employed. Reactions areconducted at temperatures ranging from −45 degrees C. up to the refluxtemperature of the alcohol employed; preferred temperature ranges arebetween −20 degrees C. and 20-25 degrees C.

The epoxide (V) is then reacted with the appropriately substitutedC-terminal amine, R_(C)—NH₂ (VI) by methods known to those skilled inthe art that opens the epoxide to produce the desired correspondingenantiomerically pure (S,R)-protected alcohol (VII). The substitutedC-terminal amines, R_(C)—NH₂ (VI) of this invention are commerciallyavailable or are known to those skilled in the art and can be readilyprepared from known compounds. R_(C) is as defined above for formula(I).

It is preferred that R_(C) is —C₁-C₈ alkyl, —(CH₂)₀₋₃—(C₃-C₇)cycloalkyl,—(CR₁₂R₁₃)₀₋₄—R_(aryl), —(CR₁₂R₁₃)₀₋₄—R_(heteroaryl),—(CR₁₂R₁₃)₀₋₄—R_(heterocycle), -cyclopentyl or -cyclohexyl ring fused toR_(aryl) or R_(heteroaryl) or R_(heterocycle).

It is more preferred that R_(C) is —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl,—(CR₁₂R₁₃)₀₋₄—R_(aryl), —(CR₁₂R₁₃)₀₋₄—R_(C-heteroaryl),—(CR₁₂R₁₃)₀₋₄—R_(heterocycle), -cyclopentyl or -cyclohexyl ring fused toa R_(aryl) or R_(heteroaryl) or R_(heterocycle).

It is even more preferred that R_(C) is —(CR₁₂R₁₃)₀₋₄—R_(aryl),—(CR₁₂R₁₃)₀₋₄—R_(heteroaryl), -cyclopentyl or -cyclohexyl ring fused toa R_(aryl) or R_(heteroaryl) or R_(heterocycle).

It is still more preferred that R_(C) is selected from the groupconsisting of —(CR₁₂R₁₃)₀₋₄—R_(aryl) where R_(aryl) is phenyl,—(CR₁₂R₁₃)₀₋₄—R_(heteroaryl), -cyclopentyl or -cyclohexyl ring fused toa R_(aryl) or R_(heteroaryl) or R_(heterocycle).

Further, it is preferred that when R_(C) is phenyl, it is substituted inthe 3-position or 3,5-positions.

Suitable reaction conditions for opening the epoxide (V) include runningthe reaction in a wide range of common and inert solvents. C₁-C₆ alcoholsolvents are preferred and isopropyl alcohol most preferred. Thereactions can be run at temperatures ranging from 20-25 degrees C. up tothe reflux temperature of the alcohol employed. The preferredtemperature range for conducting the reaction is between 50 degrees C.up to the reflux temperature of the alcohol employed. When thesubstituted C-terminal amine (VI) is a 1-amino-3,5-cis-dimethylcyclohexyldicarboxylate it is preferrably prepared as follows. Todimethyl-5-aminoisophthalate in acetic acid and methanol, is addedrhodium in alumina in a high-pressure bottle. The bottle is saturatedwith hydrogen at 55 psi and shaken for one week of time. The mixture isthen filtered through a layer of diatomaceous earth and rinsed withmethanol three times, the solvents are removed under reduced pressure(with heat) to give a concentrate. The concentrate is triturated withether and filtered again to give the desired C-terminal amine (VI).

When the substituted C-terminal amine (VI) is 1-amino-3,5-cis-dimethoxycyclohexane it is prepared by following the general procedure above andmaking non-critical variations but starting with 3,5-dimethoxyaniline.

When the substituted C-terminal amine (VI) is an aminomethyl group wherethe substituent on the methyl group is an aryl group, for exampleNH₂—CH₂—R_(C-aryl), and NH₂—CH₂—R_(C-aryl) is not commercially availableit is preferrably prepared as follows. A suitable starting material isthe (appropriately substituted) aralkyl compound. The first step isbromination of the alkyl substitutent via methods known to those skilledin the art, see for example R. C. Larock in Comprehensive OrganicTransformations, VCH Publishers, 1989, p. 313. Next the alkyl halide isreacted with azide to produce the aryl-(alkyl)-azide. Last the azide isreduced to the corresponding amine by hydrogen/catalyst to give theC-terminal amine (VI) of formula NH₂—CH₂—R_(C-aryl). The suitablyfunctionalized C-terminal amines (VI) may readily be prepared by oneskilled in the art via known methods in the literature, makingnon-significant modifications. Select literature references include 1)Calderwood, et al., Tet. Lett., 1997, 38, 1241, 2) Ciganek, J. Org.Chem., 1992, 57, 4521, 3) Thurkauf, et al., J. Med. Chem., 1990, 33,1452, 4) Werner, et al., Org. Syn., Coll. Vol. 5, 273, 5) J. Med. Chem.,1999, 42, 4193, 6) Chem. Rev. 1995, 95, 2457, 7) J. Am. Chem. Soc.,1986, 3150, 8) Felman et al., J. Med. Chem., 1992, 35, 1183, 9) J. Am.Chem. Soc. 1970, 92, 3700, 10) J. Med. Chem., 1997, 40, 2323.

One process to prepare the carboxylic acid ((IX) in CHART A and L inCHART 2A below) used in CHART A is set forth below in CHART 2A.

CHART 2A discloses an exemplary method of preparing carboxylic acid (IXand L) starting with commercially available halo nitrile (A), where X₁can be —F, —Cl, —Br, —I, or —Otf; preferably —Cl or —Br. Halo nitrile(A) and amine (B) are stirred, with heating, with solvents such as DMF,THF, NMP, dioxane, toluene and the like at temperatures up to theboiling point of the solvent, or preferably halo nitrile (A) and amine(B) are heated together in a closed vessel in the absence of solvent togive amino nitrile (C). Another method for the conversion of halonitrile (A) to amino nitrile (C) is by treating halo nitrile (A) withamine (B) in the presence of a catalyst, preferably a palladiumcatalyst, and a phosphine additive, in the presence of a base,preferably sodium tert-butoxide, and in an inert solvent, preferablytoluene, at temperatures between 20-25 degrees and the refluxtemperature of the solvent, as is known to those skilled in the art, seefor example, Acc. Chem. Res. 31, 805, (1998) and Ang. Chem. Int. Ed.Engl., 37, 2046 (1998).

Amine B used herein is commercially available or is known to thoseskilled in the art and can be readily prepared from known compounds. Rand R′ are as defined above for formula (I).

Another method for the preparation of amino nitrile (C) is to treat halonitrile (A) with tin reagent (B-1) in the presence of a palladiumcatalyst such as tris(dibenzylideneacetone)dipalladium and a phosphineadditive, preferably tris(2-methylphenyl)phosphine and an inert solventsuch as toluene at temperatures ranging from 50 to 110 degrees, as isknown to those skilled in the art, see J. Am. Chem. Soc. 116, 7901(1994), and J. Am. Chem. Soc. 116, 5969 (1994). Amino nitrile (C) isthen hydrolyzed using mineral acid or an alkaline earth base by methodswell known to those versed in the art to give amine acid (D). Amine acid(D) is then reduced to alcohol (E) in an inert solvent such as THF, attemperatures from about 20-25 degrees to reflux, using borane in formssuch as borane-methyl sulfide complex, borane-THF complex, or by usinglithium aluminum hydride in ethereal solvents such as ether or THF. Thealcohol of alcohol (E) is then converted to a leaving group X₂ (such asiodo, bromo, chloro, tosylate, mesylate, nosylate, and the like) in asolvent (such as THF, dichloromethane, DMF, toluene, ethyl acetate, oracetonitrile) to give halide (F). The leaving group X₂ of halide (F) isdisplaced with nitrile employing reagents such as sodium cyanide,potassium cyanide, and trimethylsilylcyanide in solvents such as THF,DMF, DMSO, NMP, acetonitrile, ethyl acetate and the like to give cyanide(G).

If it is desired to have additional substituents on the carbon adjacentto the acid group of carboxylic acid (IX or L), then cyanide (G) istreated with an alkali metal dialkylamide (preferably lithiumdiisopropylamide) or an alkali metal bis(trialkylsilyl)amide in inertsolvents at temperatures ranging from −78 to 20-25 degrees, followed byhalide (H), to give mono substituted nitrile (I). Halide (H) includes R₄where R₄ is as defined above for formula (I).

Halide (H) also includes X₃ such as iodo, bromo, chloro, tosylate,mesylate, nosylate and the like. Inert solvents that can be used in thestep from (G) to (I) may include, but are not limited to, acetonitrile,dialkyl ethers (preferably ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylacetamides (preferablydimethylacetamide), N,N-dialkylformamides (preferablydimethylformamide), dialkylsulfoxides (preferably dimethylsulfoxide),aromatic hydrocarbons (preferably benzene or toluene) or haloaalkanes(preferably methylene chloride).

Treatment of monosubstituted nitrile (I) with base as above and additionof halide (J) gives disubstituted nitrile (K). Halide (J) includes R₄′,where R₄′ is defined as R₄, and X₃ is as defined above. It should alsobe understood that R₄ and R₁₄ taken together can be ═O. Hydrolysis bythe methods discussed above and well known to those versed in the artgives carboxylic acid (L). If it is desired to leave the carbon adjacentto the cyano group of cyanide (G) unsubstituted, then cyanide (G) ishydrolyzed to carboxylic acid (L) using mineral acid or alkaline earthbase, by methods well known to those versed in the art.

CHART 2B discloses an exemplary method of producing other carboxylicacids (L), more particularly ones that are substituted in the 2-positionby R.

CHART 2B discloses one method of preparing carboxylic acid (L) startingwith commercially available 4-methyl-2-substituted pyridine (A), whereX₁ is halogen, preferably bromine.

4-Methyl-2-substituted pyridine (A) is oxidized to pyridine acid (B)using potassium permanganate in water and alcoholic solvent attemperatures ranging from 20-25 to 100 degrees C. or by methods asdiscussed in Smith and March, “Advanced Organic Chemistry”, Wiley, 2001,p. 1527-1528. Pyridine acid (B) is then reduced to pyridine alcohol (C)using borane in forms such as borane-methyl sulfide complex, borane-THFcomplex, or using lithium aluminum hydride in ethereal solvents such asether and THF. The alcohol of pyridine alcohol (C) is then converted toa leaving group X₂ (such as iodo, bromo, chloro, tosylate, mesylate,nosylate, triflate, and the like) in solvent (such as THF,dichloromethane, DMF, toluene, ethyl acetate, or acetonitrile) to givepyridine halide (D). Alternatively, 4-methyl-2-substituted pyridine (A)may be halogenated using halogenating agents well known to those versedin the art, including but not limited to, N-halosuccinimide and halogen,preferably N-bromosuccinimide and bromine, and others as taught in Smithand March, “Advanced Organic Chemistry”, Wiley, 2001, pp. 907-912, togive halide (D). The leaving group X₂ of pyridine halide (D) isdisplaced with nitrile by employing reagents such as sodium cyanide,potassium cyanide, or trimethylsilylcyanide in solvents such as THF,DMF, DMSO, NMP, acetonitrile, ethyl acetate and the like at temperaturesranging from 20-25 degrees C. to the boiling point of the solvent togive pyridine cyanide (E). Treatment of pyridine cyanide (E) with aboron reagent (F) such as alkylboronic acid, alkyl boronic acid ester,or alkyl boroxines in the presence of a metal catalyst with or withoutbase in an inert solvent gives alkyl pyridine (G). Alkyl pyridine (G)includes R₇, where R₇ is as defined above for formula (I).

Metal catalysts suitable for these transformations include, but are notlimited to, salts or phosphine complexes of copper, lead, or nickel suchas Cu(OAc)₂, PdCl₂ (PPh₃)₂, NiCl₂(PPh₃)₂. Bases may include, but are notlimited to, alkaline earth metal carbonates, alkaline earth metalbicarbonates, alkaline earth metal hydroxides, alkali metal carbonates,alkali metal bicarbonates, alkali metal hydroxides, alkali metalhydrides (preferably sodium hydride), alkali metal alkoxides (preferablysodium methoxide or sodium ethoxide), alkaline earth metal hydrides,alkali metal dialkylamides (preferably lithium diisopropylamide), alkalimetal bis(trialkylsilyl)amides (preferably sodiumbis(trimethylsilyl)amide), trialkyl amines (preferablydiisopropylethylamine or triethylamine) or aromatic amines (preferablypyridine). Inert solvents may include, but are not limited to,acetonitrile, dialkyl ethers (preferably ether), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacetamides(preferably dimethylacetamide), N,N-dialkylformamides (preferablydimethylformamide), dialkylsulfoxides (preferably dimethylsulfoxide),aromatic hydrocarbons (preferably benzene or toluene) or haloaalkanes(preferably methylene chloride). Preferred reaction temperatures rangefrom 20-25 degrees C. up to the boiling point of the solvent employed.Non-commercially available boronic acids or boronic acid esters may beobtained from the corresponding optionally substituted aryl halide asdescribed in Tetrahedron, 50, 979-988 (1994).

Alkyl pyridine (G) may be converted directly to carboxylic acid (L)using the hydrolysis methods as discussed above for CHART 2A and wellknown to those versed in the art. If it is desired to have additionalsubstitutions on the carbon adjacent to the acid of carboxylic acid (L),then cyanide (G) is treated with an alkali metal dialkylamide(preferably lithium diisopropylamide) or an alkali metalbis(trialkylsilyl)amide in inert solvents at temperatures ranging from−78 to 20-25 degrees C., followed by halide (H) where R₄ and X₃ aredescribed as in CHART 2A above, to give mono substituted nitrile (I).Inert solvents may include, but are not limited to, acetonitrile,dialkyl ethers (preferably ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylacetamides (preferablydimethylacetamide), N,N-dialkylformamides (preferablydimethylformamide), dialkylsulfoxides (preferably dimethylsulfoxide),aromatic hydrocarbons (preferably benzene or toluene) or haloaalkanes(preferably methylene chloride). Treatment of monosubstituted nitrile(I) with base as above and addition of halide (J) where R₄′ is describedas in CHART 2A above, gives disubstituted nitrile (K). Hydrolysis by themethods discussed above and well known to those versed in the art givescarboxylic acid (L).

An exemplary process to prepare the carboxylic acid (L) when G is notnitrogen is set forth in CHART 2C below. R₆ and R′₆ are as defined abovefor formula (I).

CHART 2C discusses one method of synthesis of phenol acid (N) whichbegins with commercially available phenol (A) or an aniline phenol (B).R′₆ in phenol (A) or aniline phenol (B) encompasses the same componentsas R₆.

When starting with the commercially available phenol (A), the protectinggroup R in the protected phenol (C) may be chosen from any protectinggroups suitable for phenols, such as those taught in Greene and Wuts,Protective Groups in Organic Synthesis, 3^(rd) ed., Wiley, 1999, pp.246-292. Protected phenol (C) is then halogenated to add X₁, usingchlorine or bromine, preferably bromine, in the presence of a Lewis acidcatalyst using methods known to those versed in the art and taught inSmith and March, Advanced Organic Chemistry, Wiley, 2001, pp. 704-707,to give halide (D).

Alternatively, the aniline of an aniline phenol (B) may first beprotected with a protecting group (step not shown) and then the phenolof an aniline phenol (B) may be protected with a different protectinggroup R, such that the protecting group on the aniline may be removed inthe presence of the phenol protecting group; such strategies oforthogonal protection are known to those versed in the art; suchprotecting groups are taught in Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) ed., Wiley, 1999. Removal of the anilineprotecting group then gives a phenol protected aniline (B-1). Phenolprotected aniline (B-1) is treated with an alkyl nitrite such as amyl orbutyl nitrite in inert solvents such as acetonitrile at temperaturesbetween −60 to 20-25 degrees C., or with sodium nitrite or potassiumnitrite in aqueous mineral acids such as aqueous sulfuric acid attemperatures between and 20-25 degrees C. (steps not shown), followed byhalide in the form of a halide salt, the preferred salts being potassiumbromide or copper bromide, to give halide (D) containing X₁ where X₁ isa halogen, preferably —Br or —Cl.

Halide (D) obtained by modification of the commercially available phenol(A) or the phenol aniline (B) is then contacted with an alkyl lithiumbase where the alkyl, represented as R′″ in acid (E), includes n-butyl,s-butyl, or t-butyl lithium in an inert solvent, preferably THF, attemperatures ranging from −78 to 0 degrees C., followed by dry carbondioxide, to give acid (E). Alternatively, halide (D) may be treated withcarbon monoxide in the presence of a catalyst, preferably a palladiumcatalyst, preferably palladium acetate, a phosphine additive, preferablytriphenyl phosphine or bis(diphenylphosphino)propane, an alcohol such asmethanol or ethanol, and a base, preferably an alkali metal carbonate oralkali metal bicarbonate, at temperatures ranging from 20-25 degrees C.to the reflux temperature of inert solvents such as toluene, DMF, NMP,and dimethylacetamide to give acid (E) where the acid is in the form ofan ester.

Acid (E), either as its acid or ester form, may then be reduced toalcohol (F) using lithium aluminum hydride in ethereal solvents such asethyl ether or THF, or acid (E) may be hydrolyzed to its acid form usingmethods well known to those versed in the art. Acid (E) in its acid formmay also be reduced to alcohol (F) using borane in such forms asborane-THF complex or borane-methyl sulfide complex in ethereal solventssuch as THF at temperatures ranging from 50 degrees C. to the refluxtemperature of the solvent. The alcohol of alcohol (F) is then convertedto a leaving group X₂ (such as iodo, bromo, chloro, tosylate, mesylate,nosylate, triflate, and the like) in solvent (such as THF,dichloromethane, DMF, toluene, ethyl acetate, or acetonitrile) attemperatures ranging between −30 and 50 degrees C. to give halo phenol(G).

The leaving group X₂ of halo phenol (G) is displaced with nitrileemploying reagents such as sodium cyanide, potassium cyanide, ortrimethylsilylcyanide in solvents such as THF, DMF, DMSO, NMP,acetonitrile, ethyl acetate and the like at temperatures between 0 and100 degrees to give nitrile (H).

Nitrile (H) may be converted directly to carboxylic acid (M) using thehydrolysis methods as discussed above for CHART 2A and well known tothose versed in the art. If it is desired to have additionalsubstitutions on the carbon adjacent to the acid of carboxylic acid (M),then nitrile (H) is treated with an alkali metal dialkylamide(preferably lithium diisopropylamide) or an alkali metalbis(trialkylsilyl)amide in inert solvents such at temperatures rangingfrom −78 to 20-25 degrees C., followed by halide (I), where R₄ and X₃are as discussed in reference to CHART 2A, to give mono-substitutednitrile (J). The inert solvents used may include, but are not limitedto, acetonitrile, dialkyl ethers (preferably ether), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylacetamides(preferably dimethylacetamide), N,N-dialkylformamides (preferablydimethylformamide), dialkylsulfoxides (preferably dimethylsulfoxide),aromatic hydrocarbons (preferably benzene or toluene) or haloaalkanes(preferably methylene chloride).

Treatment of mono-substituted nitrile (J) with base as above andaddition of halide (K), where R₄′ and X₃ are as discussed in referenceto CHART 2A, gives di-substituted nitrile (L). Hydrolysis by the methodsdiscussed above and well known to those versed in the art givescarboxylic acid (M). Removal of the protecting group of carboxylic acid(M) using, but not limited to, methods taught in Greene and Wuts,Protective Groups in Organic Synthesis, 3^(rd) ed., Wiley, 1999, pp.246-292, gives acid (N).

The compounds produced as in CHARTS 2A, 2B and 2C are then used in thesynthesis of compounds of formula (I) as exemplified by CHART A.

-   -   Examples of processes for the preparation of        N-(3-amino-2-hydroxy-propyl)-cycloalkyl- and        heterocyclyl-alkylamide compounds of formula (I), formula (Ic)        and (Id) are set forth in CHARTS 2A through 2E, which are        described in greater detail hereinbelow. For purposes of the        schemes, R₇, R₈′ and R₈″ are as defined above for R₆, R′₆ and        R″₆ in formula; and R, R₁, R₂, R₃ and R_(c) are as defined above        for formula (I).

CHART 3A discloses a process to prepare hydroxyethylamine compounds ofFormula (I) having an oxopiperazine moiety starting from a suitablyprotected oxopiperazine. Commercially available oxopiperazine (1) wherethe protecting group is benzyloxycarbonyl is treated with a base such assodium hydride and an alkyl halide to provide piperazine (2). Theprotecting group is removed, for the benzyloxycarbonyl protecting groupa palladium catalyst and hydrogen is used, to give compound (3).Compound (3) is alkylated with an α-halo alkyl ester to provideintermediate (4), which is hydrolyzed to the acid (5). Oxopiperazineacid (5) is coupled to amine (6) using a coupling agent, many of whichare known to those skilled in the art, to provide compound (7), whichhas Formula (I).

CHART 3B discloses a process to prepare hydroxyethylamine compounds ofFormula (I) having an oxopiperazine moiety starting from commerciallyavailable, literature or readily available protected amino acidderivatives (a variety of methods can be found in; Synthesis ofOptically Active α-Amino Acids, Williams, M. Robert, 1989, PergamonPress). Commercially available, literature or readily available aminoacid (8) is treated with benzylamine and a coupling agent, many whichare known to those skilled in the art, to provide derivative (9).Intermediate (9) is reduced with a reducing reagent such as lithiumaluminum hydride to give amine (10), which is alkylated with an α-haloalkyl ester to provide (11). Treatment of (11) with an acid such astrifluoroacetic acid gives oxopiperazine (12). Treatment of (12) with abase such as sodium hydride and an alkyl halide gives oxopiperazine(13). Removal of the benzyl group with hydrogen and a palladium catalystprovides intermediate (14), which is alkylated with an α-halo alkylester to give compound (15). Hydrolysis of (15) provides theoxopiperazine acid (16). Coupling of acid (16) with amine (6) using acoupling agent, many which are known to those skilled in the art, givesthe desired compound (17), which has Formula (I).

CHART 3C discloses a process to prepare hydroxyethylamine compounds ofFormula (I) having a dioxopiperazine moiety starting from commerciallyavailable, literature or readily available amino acid derivatives (avariety of methods can be found in; Synthesis of Optically Activeα-Amino Acids, Williams, M. Robert, 1989, Pergamon Press). Commerciallyavailable, literature or readily available amino acid (8) is treatedwith N-benzylglycine ethyl ester (18) and a coupling agent, many whichare known to those skilled in the art, to provide derivative (19).Treatment of (19) with an acid such as trifluoroacetic acid givesdioxopiperazine (20). Treatment of (20) with a base such as sodiumhydride and an alkyl halide gives dioxopiperazine (21). Removal of thebenzyl group with hydrogen and a palladium catalyst providesintermediate (22), which is alkylated with an alpha-halo alkyl ester togive compound (23). Hydrolysis of (23) provides the acid (24). Couplingof acid (24) with amine (6) using a coupling agent, many of which areknown to those skilled in the art, provides the desired compound (25),which has Formula (I).

CHART 3D discloses a process to prepare hydroxyethylamine compounds ofFormula (I) having a dioxopiperazine moiety starting from previouslydescribed amine (10) of CHART 2B. Amine (10) is treated with acid suchas trifluoroacetic acid to provide diamine (26). Condensation with anoxalic acid derivative gives the dioxopiperazine (27). Treatment of (27)with a base such as sodium hydride and an alkyl halide givesdioxopiperazine (28). Removal of the benzyl group with hydrogen and apalladium catalyst provides intermediate (29), which is alkylated withan α-halo alkyl ester to give compound (30). Hydrolysis of (30) providesthe acid (31). Coupling of acid (31) with amine (6) using a couplingagent, many of which are known to those skilled in the art, provides thedesired compound (32), which has Formula (I).

CHART 3E discloses a process to prepare hydroxyethylamine compounds ofFormula (I) having a dioxopiperazine moiety starting from a suitablyprotected oxopiperazine. Commercially available dioxopiperazine (33),where the protecting group is benzyl, is treated with a base such aspotassium carbonate and an alkyl halide to provide dioxopiperazine (34).The protecting group is removed (for the benzyl protecting group apalladium catalyst and hydrogen is used) to give compound (35). Compound(35) is alkylated with an α-halo alkyl ester to provide intermediate(36), which is hydrolyzed to the dioxopiperazine acid (37). Acid (37) iscoupled to amine (6) using a coupling agent, many of which are known tothose skilled in the art, to provide the desired compound (38), whichhas Formula (I).

The compounds of formula (I) are amines, and as such form salts whenreacted with acids. Pharmaceutically acceptable salts are preferred overthe corresponding amines of formula (I) since they produce compoundswhich are more water soluble, stable and/or more crystalline.Pharmaceutically acceptable salts are any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. Pharmaceutically acceptable saltsinclude acid addition salts of both inorganic and organic acids. Thepreferred pharmaceutically acceptable salts include salts of thefollowing acids acetic, aspartic, benzenesulfonic, benzoic, bicarbonic,bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic,chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic,fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic,hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic,hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic,malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic,muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic,pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric,phthalic, polygalactouronic, propionic, salicylic, stearic, succinic,succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric,teoclic and toluenesulfonic. For other acceptable salts, see Int. J.Pharm., 33, 201-217 (1986) and J. Pharm. Sci., 66(1), 1, (1977).

Methods of the Invention

The compounds of the invention, and pharmaceutically acceptable saltsthereof, are useful for treating humans or animals suffering from acondition characterized by a pathological form of beta-amyloid peptide,such as beta-amyloid plaques, and for helping to prevent or delay theonset of such a condition. For example, the compounds are useful fortreating Alzheimer's disease, for helping prevent or delay the onset ofAlzheimer's disease, for treating patients with MCI (mild cognitiveimpairment) and preventing or delaying the onset of Alzheimer's diseasein those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobal hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, and diffuse Lewy body type Alzheimer's disease. Thecompounds and compositions of the invention are particularly useful fortreating or preventing Alzheimer's disease. When treating or preventingthese diseases, the compounds of the invention can either be usedindividually or in combination, as is best for the patient.

As used herein, the term “treating” means that the compounds of theinvention can be used in humans with at least a tentative diagnosis ofdisease. The compounds of the invention will delay or slow theprogression of the disease thereby giving the individual a more usefullife span.

The term “preventing” means that the compounds of the present inventionare useful when administered to a patient who has not been diagnosed aspossibly having the disease at the time of administration, but who wouldnormally be expected to develop the disease or be at increased risk forthe disease. The compounds of the invention will slow the development ofdisease symptoms, delay the onset of the disease, or prevent theindividual from developing the disease at all. Preventing also includesadministration of the compounds of the invention to those individualsthought to be predisposed to the disease due to age, familial history,genetic or chromosomal abnormalities, and/or due to the presence of oneor more biological markers for the disease, such as a known geneticmutation of APP or APP cleavage products in brain tissues or fluids.

In treating or preventing the above diseases, the compounds of theinvention are administered in a therapeutically effective amount. Thetherapeutically effective amount will vary depending on the particularcompound used and the route of administration, as is known to thoseskilled in the art.

In treating a patient displaying any of the diagnosed above conditions aphysician may administer a compound of the invention immediately andcontinue administration indefinitely, as needed. In treating patientswho are not diagnosed as having Alzheimer's disease, but who arebelieved to be at substantial risk for Alzheimer's disease, thephysician should preferably start treatment when the patient firstexperiences early pre-Alzheimer's symptoms such as, memory or cognitiveproblems associated with aging. In addition, there are some patients whomay be determined to be at risk for developing Alzheimer's through thedetection of a genetic marker such as APOE4 or other biologicalindicators that are predictive for Alzheimer's disease. In thesesituations, even though the patient does not have symptoms of thedisease, administration of the compounds of the invention may be startedbefore symptoms appear, and treatment may be continued indefinitely toprevent or delay the outset of the disease.

Dosage Forms and Amounts

The compounds of the invention can be administered orally,parenternally, (IV, IM, depo-IM, SQ, and depo SQ), sublingually,intranasally (inhalation), intrathecally, topically, or rectally. Dosageforms known to those of skill in the art are suitable for delivery ofthe compounds of the invention.

Compositions are provided that contain therapeutically effective amountsof the compounds of the invention. The compounds are preferablyformulated into suitable pharmaceutical preparations such as tablets,capsules, or elixirs for oral administration or in sterile solutions orsuspensions for parenternal administration. Typically the compoundsdescribed above are formulated into pharmaceutical compositions usingtechniques and procedures well known in the art.

About 1 to 500 mg of a compound or mixture of compounds of the inventionor a physiologically acceptable salt or ester is compounded with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in a unit dosage form as calledfor by accepted pharmaceutical practice. The amount of active substancein those compositions or preparations is such that a suitable dosage inthe range indicated is obtained. The compositions are preferablyformulated in a unit dosage form, each dosage containing from about 2 toabout 100 mg, more preferably about 10 to about 30 mg of the activeingredient. The term “unit dosage from” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

To prepare compositions, one or more compounds of the invention aremixed with a suitable pharmaceutically acceptable carrier. Upon mixingor addition of the compound(s), the resulting mixture may be a solution,suspension, emulsion, or the like. Liposomal suspensions may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. The form of theresulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the compound inthe selected carrier or vehicle. The effective concentration issufficient for lessening or ameliorating at least one symptom of thedisease, disorder, or condition treated and may be empiricallydetermined.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds provided herein include any such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. In addition, the active materials can also be mixed withother active materials that do not impair the desired action, or withmaterials that supplement the desired action, or have another action.The compounds may be formulated as the sole pharmaceutically activeingredient in the composition or may be combined with other activeingredients.

Where the compounds exhibit insufficient solubility, methods forsolubilizing may be used. Such methods are known and include, but arenot limited to, using cosolvents such as dimethylsulfoxide (DMSO), usingsurfactants such as Tween®, and dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as salts or prodrugs mayalso be used in formulating effective pharmaceutical compositions.

The concentration of the compound is effective for delivery of an amountupon administration that lessens or ameliorates at least one symptom ofthe disorder for which the compound is administered. Typically, thecompositions are formulated for single dosage administration.

The compounds of the invention may be prepared with carriers thatprotect them against rapid elimination from the body, such astime-release formulations or coatings. Such carriers include controlledrelease formulations, such as, but not limited to, microencapsulateddelivery systems. The active compound is included in thepharmaceutically acceptable carrier in an amount sufficient to exert atherapeutically useful effect in the absence of undesirable side effectson the patient treated. The therapeutically effective concentration maybe determined empirically by testing the compounds in known in vitro andin vivo model systems for the treated disorder.

The compounds and compositions of the invention can be enclosed inmultiple or single dose containers. The enclosed compounds andcompositions can be provided in kits, for example, including componentparts that can be assembled for use. For example, a compound inhibitorin lyophilized form and a suitable diluent may be provided as separatedcomponents for combination prior to use. A kit may include a compoundinhibitor and a second therapeutic agent for co-administration. Theinhibitor and second therapeutic agent may be provided as separatecomponent parts. A kit may include a plurality of containers, eachcontainer holding one or more unit dose of the compound of theinvention. The containers are preferably adapted for the desired mode ofadministration, including, but not limited to tablets, gel capsules,sustained-release capsules, and the like for oral administration; depotproducts, pre-filled syringes, ampules, vials, and the like forparenternal administration; and patches, medipads, creams, and the likefor topical administration.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the active compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

If oral administration is desired, the compound should be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an ediblecarrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules, or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches, and the like can contain any ofthe following ingredients or compounds of a similar nature: a bindersuch as, but not limited to, gum tragacanth, acacia, corn starch, orgelatin; an excipient such as microcrystalline cellulose, starch, orlactose; a disintegrating agent such as, but not limited to, alginicacid and corn starch; a lubricant such as, but not limited to, magnesiumstearate; a gildant, such as, but not limited to, colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; and aflavoring agent such as peppermint, methyl salicylate, or fruitflavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials, whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, chewing gum orthe like. A syrup may contain, in addition to the active compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings, and flavors.

The active materials can also be mixed with other active materials thatdo not impair the desired action, or with materials that supplement thedesired action.

Solutions or suspensions used for parenternal, intradermal,subcutaneous, or topical application can include any of the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oil, a naturally occurring vegetable oil such as sesameoil, coconut oil, peanut oil, cottonseed oil, and the like, or asynthetic fatty vehicle such as ethyl oleate, and the like, polyethyleneglycol, glycerine, propylene glycol, or other synthetic solvent;antimicrobial agents such as benzyl alcohol and methyl parabens;antioxidants such as ascorbic acid and sodium bisulfite; chelatingagents such as ethylenediaminetetraacetic acid (EDTA); buffers such asacetates, citrates, and phosphates; and agents for the adjustment oftonicity such as sodium chloride and dextrose. Parenternal preparationscan be enclosed in ampoules, disposable syringes, or multiple dose vialsmade of glass, plastic, or other suitable material. Buffers,preservatives, antioxidants, and the like can be incorporated asrequired.

Where administered intravenously, suitable carriers includephysiological saline, phosphate buffered saline (PBS), and solutionscontaining thickening and solubilizing agents such as glucose,polyethylene glycol, polypropyleneglycol, and mixtures thereof.Liposomal suspensions including tissue-targeted liposomes may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known for example, as described in U.S. Pat. No.4,522,811.

The active compounds may be prepared with carriers that protect thecompound against rapid elimination from the body, such as time-releaseformulations or coatings. Such carriers include controlled releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid, and the like.Methods for preparation of such formulations are known to those skilledin the art.

The compounds of the invention can be administered orally, parenternally(IV, IM, depo-IM, SQ, and depo-SQ), sublingually, intranasally(inhalation), intrathecally, topically, or rectally. Dosage forms knownto those skilled in the art are suitable for delivery of the compoundsof the invention.

Compounds of the invention may be administered enterally orparenterally. When administered orally, compounds of the invention canbe administered in usual dosage forms for oral administration as is wellknown to those skilled in the art. These dosage forms include the usualsolid unit dosage forms of tablets and capsules as well as liquid dosageforms such as solutions, suspensions, and elixirs. When the solid dosageforms are used, it is preferred that they be of the sustained releasetype so that the compounds of the invention need to be administered onlyonce or twice daily.

The oral dosage forms are administered to the patient 1, 2, 3, or 4times daily. It is preferred that the compounds of the invention beadministered either three or fewer times, more preferably once or twicedaily. Hence, it is preferred that the compounds of the invention beadministered in oral dosage form. It is preferred that whatever oraldosage form is used, that it be designed so as to protect the compoundsof the invention from the acidic environment of the stomach. Entericcoated tablets are well known to those skilled in the art. In addition,capsules filled with small spheres each coated to protect from theacidic stomach, are also well known to those skilled in the art.

When administered orally, an administered amount therapeuticallyeffective to inhibit beta-secretase activity, to inhibit A betaproduction, to inhibit A beta deposition, or to treat or prevent AD isfrom about 0.1 mg/day to about 1,000 mg/day. It is preferred that theoral dosage is from about 1 mg/day to about 100 mg/day. It is morepreferred that the oral dosage is from about 5 mg/day to about 50mg/day. It is understood that while a patient may be started at onedose, that dose may be varied over time as the patient's conditionchanges.

Compounds of the invention may also be advantageously delivered in anano crystal dispersion formulation. Preparation of such formulations isdescribed, for example, in U.S. Pat. No. 5,145,684. Nano crystallinedispersions of HIV protease inhibitors and their method of use aredescribed in U.S. Pat. No. 6,045,829. The nano crystalline formulationstypically afford greater bioavailability of drug compounds.

The compounds of the invention can be administered parenterally, forexample, by IV, IM, depo-IM, SC, or depo-SC. When administeredparenterally, a therapeutically effective amount of about 0.5 to about100 mg/day, preferably from about 5 to about 50 mg daily should bedelivered. When a depot formulation is used for injection once a monthor once every two weeks, the dose should be about 0.5 mg/day to about 50mg/day, or a monthly dose of from about 15 mg to about 1,500 mg. In partbecause of the forgetfulness of the patients with Alzheimer's disease,it is preferred that the parenteral dosage form be a depo formulation.

The compounds of the invention can be administered sublingually. Whengiven sublingually, the compounds of the invention should be given oneto four times daily in the amounts described above for IMadministration.

The compounds of the invention can be administered intranasally. Whengiven by this route, the appropriate dosage forms are a nasal spray ordry powder, as is known to those skilled in the art. The dosage of thecompounds of the invention for intranasal administration is the amountdescribed above for IM administration.

The compounds of the invention can be administered intrathecally. Whengiven by this route the appropriate dosage form can be a parenternaldosage form as is known to those skilled in the art. The dosage of thecompounds of the invention for intrathecal administration is the amountdescribed above for IM administration.

The compounds of the invention can be administered topically. When givenby this route, the appropriate dosage form is a cream, ointment, orpatch. Because of the amount of the compounds of the invention to beadministered, the patch is preferred. When administered topically, thedosage is from about 0.5 mg/day to about 200 mg/day. Because the amountthat can be delivered by a patch is limited, two or more patches may beused. The number and size of the patch is not important, what isimportant is that a therapeutically effective amount of the compounds ofthe invention be delivered as is known to those skilled in the art. Thecompounds of the invention can be administered rectally by suppositoryas is known to those skilled in the art. When administered bysuppository, the therapeutically effective amount is from about 0.5 mgto about 500 mg.

The compounds of the invention can be administered by implants as isknown to those skilled in the art. When administering a compound of theinvention by implant, the therapeutically effective amount is the amountdescribed above for depot administration.

The invention here is the new compounds of the invention and new methodsof using the compounds of the invention. Given a particular compound ofthe invention and a desired dosage form, one skilled in the art wouldknow how to prepare and administer the appropriate dosage form.

The compounds of the invention are used in the same manner, by the sameroutes of administration, using the same pharmaceutical dosage forms,and at the same dosing schedule as described above, for preventingdisease or treating patients with MCI (mild cognitive impairment) andpreventing or delaying the onset of Alzheimer's disease in those whowould progress from MCI to AD, for treating or preventing Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, and diffuse Lewy body type of Alzheimer's disease.

The compounds of the invention can be used in combination, with eachother or with other therapeutic agents or approaches used to treat orprevent the conditions listed above. Such agents or approaches include:acetylcholine esterase inhibitors such as tacrine(tetrahydroaminoacridine, marketed as COGNEX®), donepezil hydrochloride,(marketed as Aricept® and rivastigmine (marketed as Exelon®);gamma-secretase inhibitors; anti-inflammatory agents such ascyclooxygenase II inhibitors; anti-oxidants such as Vitamin E andginkolides; immunological approaches, such as, for example, immunizationwith A beta peptide or administration of anti-A beta peptide antibodies;statins; and direct or indirect neurotropic agents such asCerebrolysin®, AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454), and otherneurotropic agents of the future.

In addition, the compounds of the present invention can also be usedwith inhibitors of P-glycoproten (P-gp). The use of P-gp inhibitors isknown to those skilled in the art. See for example, Cancer Research, 53,4595-4602 (1993), Clin. Cancer Res., 2, 7-12 (1996), Cancer Research,56, 4171-4179 (1996), International Publications WO99/64001 andWO01/10387. The important thing is that the blood level of the P-gpinhibitor be such that it exerts its effect in inhibiting P-gp fromdecreasing brain blood levels of the compounds of the present invention.To that end the P-gp inhibitor and the compounds of the presentinvention can be administered at the same time, by the same or differentroute of administration, or at different times. The important thing isnot the time of administration but having an effective blood level ofthe P-gp inhibitor.

Suitable P-gp inhibitors include cyclosporin A, verapamil, tamoxifen,quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate, progesterone,rapamycin, 10,11-methanodibenzosuberane, phenothiazines, acridinederivatives such as GF120918, FK506, VX-710, LY335979, PSC-833,GF-102,918 and other steroids. It is to be understood that additionalagents will be found that do the same function and are also consideredto be useful.

The P-gp inhibitors can be administered orally, parenterally, (IV, IM,IM-depo, SQ, SQ-depo), topically, sublingually, rectally, intranasally,intrathecally and by implant.

The therapeutically effective amount of the P-gp inhibitors is fromabout 0.1 to about 300 mg/kg/day, preferably about 0.1 to about 150mg/kg daily. It is understood that while a patient may be started on onedose, that dose may have to be varied over time as the patient'scondition changes.

When administered orally, the P-gp inhibitors can be administered inusual dosage forms for oral administration as is known to those skilledin the art. These dosage forms include the usual solid unit dosage formsof tablets and capsules as well as liquid dosage forms such assolutions, suspensions and elixirs. When the solid dosage forms areused, it is preferred that they be of the sustained release type so thatthe P-gp inhibitors need to be administered only once or twice daily.The oral dosage forms are administered to the patient one thru fourtimes daily. It is preferred that the P-gp inhibitors be administeredeither three or fewer times a day, more preferably once or twice daily.Hence, it is preferred that the P-gp inhibitors be administered in soliddosage form and further it is preferred that the solid dosage form be asustained release form which permits once or twice daily dosing. It ispreferred that what ever dosage form is used, that it be designed so asto protect the P-gp inhibitors from the acidic environment of thestomach. Enteric coated tablets are well known to those skilled in theart. In addition, capsules filled with small spheres each coated toprotect from the acidic stomach, are also well known to those skilled inthe art.

In addition, the P-gp inhibitors can be administered parenterally. Whenadministered parenterally they can be administered IV, IM, depo-IM, SQor depo-SQ.

The P-gp inhibitors can be given sublingually. When given sublingually,the P-gp inhibitors should be given one thru four times daily in thesame amount as for IM administration.

The P-gp inhibitors can be given intranasally. When given by this routeof administration, the appropriate dosage forms are a nasal spray or drypowder as is known to those skilled in the art. The dosage of the P-gpinhibitors for intranasal administration is the same as for IMadministration.

The P-gp inhibitors can be given intrathecally. When given by this routeof administration the appropriate dosage form can be a parenteral dosageform as is known to those skilled in the art.

The P-gp inhibitors can be given topically. When given by this route ofadministration, the appropriate dosage form is a cream, ointment orpatch. Because of the amount of the P-gp inhibitors needed to beadministered the patch is preferred. However, the amount that can bedelivered by a patch is limited. Therefore, two or more patches may berequired. The number and size of the patch is not important, what isimportant is that a therapeutically effective amount of the P-gpinhibitors be delivered as is known to those skilled in the art.

The P-gp inhibitors can be administered rectally by suppository as isknown to those skilled in the art.

The P-gp inhibitors can be administered by implants as is known to thoseskilled in the art.

There is nothing novel about the route of administration or the dosageforms for administering the P-gp inhibitors. Given a particular P-gpinhibitor, and a desired dosage form, one skilled in the art would knowhow to prepare the appropriate dosage form for the P-gp inhibitor.

It should be apparent to one skilled in the art that the exact dosageand frequency of administration will depend on the particular compoundsof the invention administered, the particular condition being treated,the severity of the condition being treated, the age, weight, generalphysical condition of the particular patient, and other medication theindividual may be taking as is well known to administering physicianswho are skilled in this art.

Inhibition of APP Cleavage

The compounds of the invention inhibit cleavage of APP between Met595and Asp596 numbered for the APP695 isoform, or a mutant thereof, or at acorresponding site of a different isoform, such as APP751 or APP770, ora mutant thereof (sometimes referred to as the “beta secretase site”).While not wishing to be bound by a particular theory, inhibition ofbeta-secretase activity is thought to inhibit production of beta amyloidpeptide (A beta). Inhibitory activity is demonstrated in one of avariety of inhibition assays, whereby cleavage of an APP substrate inthe presence of a beta-secretase enzyme is analyzed in the presence ofthe inhibitory compound, under conditions normally sufficient to resultin cleavage at the beta-secretase cleavage site. Reduction of APPcleavage at the beta-secretase cleavage site compared with an untreatedor inactive control is correlated with inhibitory activity. Assaysystems that can be used to demonstrate efficacy of the compoundinhibitors of the invention are known. Representative assay systems aredescribed, for example, in U.S. Pat. Nos. 5,942,400, 5,744,346, as wellas in the Examples below.

The enzymatic activity of beta-secretase and the production of A betacan be analyzed in vitro or in vivo, using natural, mutated, and/orsynthetic APP substrates, natural, mutated, and/or synthetic enzyme, andthe test compound. The analysis may involve primary or secondary cellsexpressing native, mutant, and/or synthetic APP and enzyme, animalmodels expressing native APP and enzyme, or may utilize transgenicanimal models expressing the substrate and enzyme. Detection ofenzymatic activity can be by analysis of one or more of the cleavageproducts, for example, by immunoassay, fluorometric or chromogenicassay, HPLC, or other means of detection. Inhibitory compounds aredetermined as those having the ability to decrease the amount ofbeta-secretase cleavage product produced in comparison to a control,where beta-secretase mediated cleavage in the reaction system isobserved and measured in the absence of inhibitory compounds.

Beta-Secretase

Various forms of beta-secretase enzyme are known, and are available anduseful for assay of enzyme activity and inhibition of enzyme activity.These include native, recombinant, and synthetic forms of the enzyme.Human beta-secretase is known as Beta Site APP Cleaving Enzyme (BACE),Asp2, and memapsin 2, and has been characterized, for example, in U.S.Pat. No. 5,744,346 and published PCT patent applications WO98/22597,WO00/03819, WO01/23533, and WO00/17369, as well as in literaturepublications (Hussain et. al., 1999, Mol. Cell. Neurosci. 14:419-427;Vassar et. al., 1999, Science 286:735-741; Yan et. al., 1999, Nature402:533-537; Sinha et. al., 1999, Nature 40:537-540; and Lin et. al.,2000, PNAS USA 97:1456-1460). Synthetic forms of the enzyme have alsobeen described (WO98/22597 and WO00/17369). Beta-secretase can beextracted and purified from human brain tissue and can be produced incells, for example mammalian cells expressing recombinant enzyme.

Preferred compounds are effective to inhibit 50% of beta-secretaseenzymatic activity at a concentration of less than 50 micromolar,preferably at a concentration of 10 micromolar or less, more preferably1 micromolar or less, and most preferably 10 nanomolar or less.

APP Substrate

Assays that demonstrate inhibition of beta-secretase-mediated cleavageof APP can utilize any of the known forms of APP, including the 695amino acid “normal” isotype described by Kang et. al., 1987, Nature325:733-6, the 770 amino acid isotype described by Kitaguchi et. al.,1981, Nature 331:530-532, and variants such as the Swedish Mutation(KM670-1NL) (APP-SW), the London Mutation (V7176F), and others. See, forexample, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature Genet.1:233-234, for a review of known variant mutations. Additional usefulsubstrates include the dibasic amino acid modification, APP-KKdisclosed, for example, in WO 00/17369, fragments of APP, and syntheticpeptides containing the beta-secretase cleavage site, wild type (WT) ormutated form, e.g., SW, as described, for example, in U.S. Pat. No.5,942,400 and WO00/03819.

The APP substrate contains the beta-secretase cleavage site of APP(KM-DA or NL-DA) for example, a complete APP peptide or variant, an APPfragment, a recombinant or synthetic APP, or a fusion peptide.Preferably, the fusion peptide includes the beta-secretase cleavage sitefused to a peptide having a moiety useful for enzymatic assay, forexample, having isolation and/or detection properties. Such moieties,include for example, an antigenic epitope for antibody binding, a labelor other detection moiety, a binding substrate, and the like.

Antibodies

Products characteristic of APP cleavage can be measured by immunoassayusing various antibodies, as described, for example, in Pirttila et.al., 1999, Neuro. Lett. 249:21-4, and in U.S. Pat. No. 5,612,486. Usefulantibodies to detect A beta include, for example, the monoclonalantibody 6E10 (Senetek, St. Louis, Mo.) that specifically recognizes anepitope on amino acids 1-16 of the A beta peptide; antibodies 162 and164 (New York State Institute for Basic Research, Staten Island, N.Y.)that are specific for human A beta 1-40 and 1-42, respectively; andantibodies that recognize the junction region of beta-amyloid peptide,the site between residues 16 and 17, as described in U.S. Pat. No.5,593,846. Antibodies raised against a synthetic peptide of residues 591to 596 of APP and SW192 antibody raised against 590-596 of the Swedishmutation are also useful in immunoassay of APP and its cleavageproducts, as described in U.S. Pat. Nos. 5,604,102 and 5,721,130.

Assay Systems

Assays for determining APP cleavage at the beta-secretase cleavage siteare well known in the art. Exemplary assays, are described, for example,in U.S. Pat. Nos. 5,744,346 and 5,942,400, and described in the Examplesbelow.

Cell Free Assays

Exemplary assays that can be used to demonstrate the inhibitory activityof the compounds of the invention are described, for example, inWO0/17369, WO 00/03819, and U.S. Pat. Nos. 5,942,400 and 5,744,346. Suchassays can be performed in cell-free incubations or in cellularincubations using cells expressing a beta-secretase and an APP substratehaving a beta-secretase cleavage site.

An APP substrate containing the beat-secretase cleavage site of APP, forexample, a complete APP or variant, an APP fragment, or a recombinant orsynthetic APP substrate containing the amino acid sequence: KM-DA orNL-DA, is incubated in the presence of beta-secretase enzyme, a fragmentthereof, or a synthetic or recombinant polypeptide variant havingbeta-secretase activity and effective to cleave the beta-secretasecleavage site of APP, under incubation conditions suitable for thecleavage activity of the enzyme. Suitable substrates optionally includederivatives that may be fusion proteins or peptides that contain thesubstrate peptide and a modification useful to facilitate thepurification or detection of the peptide or its beta-secretase cleavageproducts. Useful modifications include the insertion of a knownantigenic epitope for antibody binding; the linking of a label ordetectable moiety, the linking of a binding substrate, and the like.

Suitable incubation conditions for a cell-free in vitro assay include,for example: approximately 200 nanomolar to 10 micromolar substrate,approximately 10 to 200 picomolar enzyme, and approximately 0.1nanomolar to 10 micromolar inhibitor compound, in aqueous solution, atan approximate pH of 4-7, at approximately 37 degrees C., for a timeperiod of approximately 10 minutes to 3 hours. These incubationconditions are exemplary only, and can be varied as required for theparticular assay components and/or desired measurement system.Optimization of the incubation conditions for the particular assaycomponents should account for the specific beta-secretase enzyme usedand its pH optimum, any additional enzymes and/or markers that might beused in the assay, and the like. Such optimization is routine and willnot require undue experimentation.

One useful assay utilizes a fusion peptide having maltose bindingprotein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBPportion is captured on an assay substrate by anti-MBP capture antibody.Incubation of the captured fusion protein in the presence ofbeta-secretase results in cleavage of the substrate at thebeta-secretase cleavage site. Analysis of the cleavage activity can be,for example, by immunoassay of cleavage products. One such immunoassaydetects a unique epitope exposed at the carboxy terminus of the cleavedfusion protein, for example, using the antibody SW192. This assay isdescribed, for example, in U.S. Pat. No. 5,942,400.

Cellular Assay

Numerous cell-based assays can be used to analyze beta-secretaseactivity and/or processing of APP to release A beta. Contact of an APPsubstrate with a beta-secretase enzyme within the cell and in thepresence or absence of a compound inhibitor of the invention can be usedto demonstrate beta-secretase inhibitory activity of the compound.Preferably, assay in the presence of a useful inhibitory compoundprovides at least about 30%, most preferably at least about 50%inhibition of the enzymatic activity, as compared with a non-inhibitedcontrol.

In one embodiment, cells that naturally express beta-secretase are used.Alternatively, cells are modified to express a recombinantbeta-secretase or synthetic variant enzyme as discussed above. The APPsubstrate may be added to the culture medium and is preferably expressedin the cells. Cells that naturally express APP, variant or mutant formsof APP, or cells transformed to express an isoform of APP, mutant orvariant APP, recombinant or synthetic APP, APP fragment, or syntheticAPP peptide or fusion protein containing the beta-secretase APP cleavagesite can be used, provided that the expressed APP is permitted tocontact the enzyme and enzymatic cleavage activity can be analyzed.

Human cell lines that normally process A beta from APP provide a usefulmeans to assay inhibitory activities of the compounds of the invention.Production and release of A beta and/or other cleavage products into theculture medium can be measured, for example by immunoassay, such asWestern blot or enzyme-linked immunoassay (EIA) such as by ELISA.

Cells expressing an APP substrate and an active beta-secretase can beincubated in the presence of a compound inhibitor to demonstrateinhibition of enzymatic activity as compared with a control. Activity ofbeta-secretase can be measured by analysis of one or more cleavageproducts of the APP substrate. For example, inhibition of beta-secretaseactivity against the substrate APP would be expected to decrease releaseof specific beta-secretase induced APP cleavage products such as A beta.

Although both neural and non-neural cells process and release A beta,levels of endogenous beta-secretase activity are low and often difficultto detect by EIA. The use of cell types known to have enhancedbeta-secretase activity, enhanced processing of APP to A beta, and/orenhanced production of A beta are therefore preferred. For example,transfection of cells with the Swedish Mutant form of APP (APP-SW); withAPP-KK; or with APP-SW-KK provides cells having enhanced beta-secretaseactivity and producing amounts of A beta that can be readily measured.

In such assays, for example, the cells expressing APP and beta-secretaseare incubated in a culture medium under conditions suitable forbeta-secretase enzymatic activity at its cleavage site on the APPsubstrate. On exposure of the cells to the compound inhibitor, theamount of A beta released into the medium and/or the amount of CTF99fragments of APP in the cell lysates is reduced as compared with thecontrol. The cleavage products of APP can be analyzed, for example, byimmune reactions with specific antibodies, as discussed above.

Preferred cells for analysis of beta-secretase activity include primaryhuman neuronal cells, primary transgenic animal neuronal cells where thetransgene is APP, and other cells such as those of a stable 293 cellline expressing APP, for example, APP-SW.

In vivo Assays: Animal Models

Various animal models can be used to analyze beta-secretase activityand/or processing of APP to release A beta, as described above. Forexample, transgenic animals expressing APP substrate and beta-secretaseenzyme can be used to demonstrate inhibitory activity of the compoundsof the invention. Certain transgenic animal models have been described,for example, in U.S. Pat. Nos. 5,877,399; 5,612,486; 5,387,742;5,720,936; 5,850,003; 5,877,015, and 5,811,633, and in Ganes et. al.,1995, Nature 373:523. Preferred are animals that exhibit characteristicsassociated with the pathophysiology of AD. Administration of thecompound inhibitors of the invention to the transgenic mice describedherein provides an alternative method for demonstrating the inhibitoryactivity of the compounds. Administration of the compounds in apharmaceutically effective carrier and via an administrative route thatreaches the target tissue in an appropriate therapeutic amount is alsopreferred.

Inhibition of beta-secretase mediated cleavage of APP at thebeta-secretase cleavage site and of A beta release can be analyzed inthese animals by measure of cleavage fragments in the animal's bodyfluids such as cerebral fluid or tissues. Analysis of brain tissues forA beta deposits or plaques is preferred.

On contacting an APP substrate with a beta-secretase enzyme in thepresence of an inhibitory compound of the invention and under conditionssufficient to permit enzymatic mediated cleavage of APP and/or releaseof A beta from the substrate, the compounds of the invention areeffective to reduce beta-secretase-mediated cleavage of APP at thebeta-secretase cleavage site and/or effective to reduce released amountsof A beta. Where such contacting is the administration of the inhibitorycompounds of the invention to an animal model, for example, as describedabove, the compounds are effective to reduce A beta deposition in braintissues of the animal, and to reduce the number and/or size of betaamyloid plaques. Where such administration is to a human subject, thecompounds are effective to inhibit or slow the progression of diseasecharacterized by enhanced amounts of A beta, to slow the progression ofAD in the, and/or to prevent onset or development of AD in a patient atrisk for the disease.

DEFINITIONS/ABBREVIATIONS

The following abbreviations/definitions are used interchangeably herein:

All temperatures are in degrees Celsius (° C.).

TLC refers to thin-layer chromatography.

psi refers to pounds/in².

h refers to hours.

HPLC refers to high pressure liquid chromatography.

THF refers to tetrahydrofuran.

LDA refers to lithium diisopropylamide

DMF refers to dimethylformamide.

DIPEA refers to diisopropylethylamine

EDC refers to ethyl-1-(3-dimethylaminopropyl)carbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

HOBt refers to 1-hydroxy benzotriazole.

HOAt refers to 1-Hydroxy-7-azabenzotriazole.

HATU refers toO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

NMM refers to N-methylmorpholine.

NBS refers to N-bromosuccinimide.

TEA refers to triethylamine.

BOC refers to 1,1-dimethylethoxy carbonyl or t-butoxycarbonyl,—CO—O—C(CH₃)₃.

CBZ refers to benzyloxycarbonyl, —CO—O—CH₂-phenyl.

FMOC refers to 9-fluorenylmethyl carbonate.

TFA refers to trifluoracetic acid, CF₃—COOH.

CDI refers to 1,1′-carbonyldiimidazole.

Saline refers to an aqueous saturated sodium chloride solution.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (d) downfield from TMS.

IR refers to infrared spectroscopy.

-phenyl refers to phenyl (C₆H₅).

MS refers to mass spectrometry expressed as m/e, m/z or mass/chargeunit. MH⁺ refers to the positive ion of a parent plus a hydrogen atom.EI refers to electron impact. CI refers to chemical ionization. FABrefers to fast atom bombardment.

HRMS refers to high resolution mass spectrometry.

Ether refers to diethyl ether.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate.

TBDMSCl refers to t-butyldimethylsilyl chloride.

TBDMSOTf refers to t-butyldimethylsilyl trifluosulfonic acid ester.

Trisomy 21 refers to Down's Syndrome.

APP, amyloid precursor protein, is defined as any APP polypeptide,including APP variants, mutations, and isoforms, for example, asdisclosed in U.S. Pat. No. 5,766,846.

A beta, amyloid beta peptide, is defined as any peptide resulting frombeta-secretase mediated cleavage of APP, including peptides of 39, 40,41, 42, and 43 amino acids, and extending from the beta-secretasecleavage site to amino acids 39, 40, 41, 42, or 43.

Beta-secretase (BACE1, Asp2, Memapsin 2) is an aspartyl protease thatmediates cleavage of APP at the amino-terminal edge of A beta. Humanbeta-secretase is described, for example, in WO00/17369.

“Pharmaceutically acceptable” refers to those properties and/orsubstances that are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

A therapeutically effective amount is defined as an amount effective toreduce or lessen at least one symptom of the disease being treated or toreduce or delay onset of one or more clinical markers or symptoms of thedisease.

The present invention provides compounds, compositions, and methods forinhibiting beta-secretase enzyme activity and A beta peptide production.Inhibition of beta-secretase enzyme activity halts or reduces theproduction of A beta from APP and reduces or eliminates the formation ofbeta-amyloid deposits in the brain.

Unless defined otherwise, all scientific and technical terms used hereinhave the same meaning as commonly understood by one of skill in the artto which this invention belongs. The disclosures in this application ofall articles and references, including patents, are incorporated hereinby reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

The starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.

EXAMPLES Synthesis Synthesis of N-(3-amino-2-hydroxy-propyl)-aryl andHeteroaryl-alkylamides of Formula (I), Formula (Ia) and Formula (Ib)

The following compounds in table 1 are prepared essentially according tothe procedures described in the schemes, examples and preparations setforth herein. The names of all compounds herein were generated at leastin part by using the Advanced Chemistry Development Inc. (ACD)nomenclature program, IUPAC Name Batch Version 4, 4.5 or 5, or ChemdrawUltra versions 6.0 or 6.02.

TABLE 1

1

5

14

16

23

29

32

35

42

52

70

86

100

115

128

133

168

187

TABLE 2 Compound No. Compound Name MS 1 N-{(1S,2R)-1-benzyl-2- 538.1994hydroxy-3-[(3- HRMS methoxybenzyl)amino]propyl}- calcd3-(1,1-dioxido-3-oxo-1,2- 538.2012 benzisothiazol-2(3H)- yl)propanamidehydrochloride 2 N-{(1S,2R)-1-benzyl-2- 488.2177 hydroxy-3-[(3- HRMSmethoxybenzyl)amino]propyl}- calcd 3-(1,3-dioxo-1,3-dihydro-2H- 488.2185isoindol-2-yl)propanamide hydrochloride 3 N-{(1S,2R)-1-benzyl-2-479.2325 hydroxy-3-[(3- HRMS methoxybenzyl)amino]propyl}- calcd4-(4-fluorophenyl)-4- 479.2346 oxobutanamide hydrochloride 4N-{(1S,2R)-1-benzyl-3-[(2,3- 437.3 dimethylcyclohexyl)amino]-2-hydroxypropyl}-3- phenylbutanamide 5 N-((1S,2R)-1-benzyl-3-{[3- 440.3(dimethylamino)-2,2- dimethylpropyl]amino}-2- hydroxypropyl)-2-phenylbutanamide 6 N-((1S,2R)-1-benzyl-3-{[3- 440.3 (dimethylamino)-2,2-dimethylpropyl]amino}-2- hydroxypropyl)-3- phenylbutanamide 7N-{(1S,2R)-1-benzyl-2- 431.3 hydroxy-3-[(1- phenylethyl)amino]propyl}-3-phenylbutanamide 8 N-{(1S,2R)-1-benzyl-2- 411.3 hydroxy-3-[(1,2,2-trimethylpropyl)amino]propyl}- 2-phenylbutanamide 9N-{(1S,2R)-1-benzyl-2- 411.3 hydroxy-3-[(1,2,2-trimethylpropyl)amino]propyl}- 3-phenylbutanamide compound with methylhydroperoxide (1:1) 10 N-{(1S,2R)-1-benzyl-3-[(1,3- 411.3dimethylbutyl)amino]-2- hydroxypropyl}-2- phenylbutanamide compound withmethyl hydroperoxide (1:1) 11 N-{(1S,2R)-1-benzyl-3-[(1,3- 411.3dimethylbutyl)amino]-2- hydroxypropyl}-3- phenylbutanamide 12N-{(1S,2R)-1-benzyl-3-[(1- 397.3 ethylpropyl)amino]-2- hydroxypropyl}-2-phenylbutanamide compound with methyl hydroperoxide (1:1) 13N-{(1S,2R)-1-benzyl-3-[(1- 397.3 ethylpropyl)amino]-2- hydroxypropyl}-3-phenylbutanamide 14 N-{(1S,2R)-1-(3,5- 635.82difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-(5-methoxy-1,2,3,4- tetrahydronaphthalen-1- yl)acetamide 152-[4-(2-amino-2- 624.33 oxoethoxy)phenyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2- hydroxy-3-[(3-iodobenzyl)amino]propyl}acetamide 16 N-{(1S,2R)-1-(3,5- 678.58difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-[4-(2-oxo-2-pyrrolidin-1- ylethoxy)phenyl]acetamide 17N-{(1S,2R)-1-(3,5- 643.86 difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 2-{4-[(methylsulfonyl)amino]phenyl}acetamide 18 N-{(1S,2R)-1-(3,5- 594.34difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-4-oxo-4-pyridin-2- ylbutanamide 19 N-{(1S,2R)-1-(3,5- 693.43difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-{4-[2-(4-methylpiperazin-1- yl)ethoxy]phenyl}acetamide 202-[3-(2-amino-2- 624.82 oxoethoxy)phenyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2- hydroxy-3-[(3-iodobenzyl)amino]propyl}acetamide 21 N-{(1S,2R)-1-(3,5- 619.51difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-4-(2,3-dihydro-1H-inden-1- yl)butanamide 22 N-{(1S,2R)-1-(3,5- 635.44difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-methyl-2-(2-methyl-2,3- dihydro-1-benzofuran-5- yl)propanamide 23N-{(1S,2R)-1-(3,5- 687.89 difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 3-hydroxy-4-phenoxy-3- phenylbutanamide 242-(1,1′-biphenyl-4-yl)-N- 655.88 {(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- [(3- iodobenzyl)amino]propyl}butanamide 25N-{(1S,2R)-1-(3,5- 671.91 difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 4-(4-phenoxyphenyl)butanamide 26N-{(1S,2R)-1-(3,5- 643.85 difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 2-(4-phenoxyphenyl)acetamide 272-[3-chloro-4-(1-oxo-1,3- 730.7 dihydro-2H-isoindol-2-yl)phenyl]-N-{(1S,2R)-1-(3,5- difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}propanamide 28 N-{(1S,2R)-1-(3,5- 621.78difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-4-(2,4-dimethylphenyl)-4- oxobutanamide 29 N-{(1S,2R)-1-(3,5- 677.83difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-4-(7-methoxy-2-methyl-1- benzofuran-4-yl)-4- oxobutanamide 304′-[4-({(1S,2R)-1-(3,5- 712.97 difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}amino)- 4-oxobutanoyl]-1,1′-biphenyl-2-carboxamide 31 N-{(1S,2R)-1-(3,5- 686.89difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}- 4-{2-[(methylsulfonyl)amino]phenyl}- 4-oxobutanamide 32(2Z)-N-{(1S,2R)-1-(3,5- 640.89 difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 2-phenyl-3-pyridin-4-ylprop- 2-enamide 33N-{(1S,2R)-1-(3,5- 682.87 difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 2-[4-(1,3-dihydro-2H- isoindol-2-yl)phenyl]propanamide 34 N-{(1S,2R)-1-(3,5- 619.91difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-(2,3-dihydro-1H-inden-5- yl)butanamide 35 N-{(1S,2R)-1-(3,5- 569.67difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-(6-oxopyridazin-1(6H)- yl)acetamide 36 N-{(1S,2R)-1-(3,5- 672.93difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-4- phenylbutanamide 37 N-{(1S,2R)-1-(3,5-623.24 difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-(4-hydroxy-5-isopropyl-2- methylphenyl)acetamide 38 N-{(1S,2R)-1-(3,5-619.38 difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-[4-(2-methylprop-1- enyl)phenyl]propanamide 39 N-{(1S,2R)-1-(3,5-675.74 difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-[4-(thien-2- ylcarbonyl)phenyl]propanamide 40 (2R)-N-{(1S,2R)-1-(3,5-645.63 difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-(6-methoxy-2- naphthyl)propanamide 41 N-{(1S,2R)-1-(3,5- 634.68difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-[4-(2-oxopyrrolidin-1- yl)phenyl]acetamide 42 N-{(1S,2R)-1-(3,5-631.75 difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-2-(3,4-dihydronaphthalen-1- yl)butanamide 43 N-{(1S,2R)-1-benzyl-2-461.2 hydroxy-3-[(3- methoxybenzyl)amino]propyl}- 2-(4-isopropylphenyl)acetamide compound with methyl hydroperoxide (1:1) 44N-{(1S,2R)-1-benzyl-2- 465.2 hydroxy-3-[(3- methoxybenzyl)amino]propyl}-2-[4- (methylthio)phenyl]acetamide 45 N-{(1S,2R)-1-(3,5- 440.2difluorobenzyl)-2-hydroxy-3- [(pyridin-2- ylmethyl)amino]propyl}-3-phenylpropanamide 46 N-{(1S,2R)-1-(3,5- 421.2difluorobenzyl)-2-hydroxy-3- [(2-methoxy-1- methylethyl)amino]propyl}-3-phenylpropanamide 47 N-{(1S,2R)-1-(3,5- 407.3difluorobenzyl)-2-hydroxy-3- [(2-hydroxy-1- methylethyl)amino]propyl}-3-phenylpropanamide compound with methyl hydroperoxide (1:1) 48N-[(1S,2R)-3-(benzylamino)-1- 439.3 (3,5-difluorobenzyl)-2-hydroxypropyl]-3- phenylpropanamide 49 N-{(1S,2R)-1-(3,5- 469.3difluorobenzyl)-2-hydroxy-3- [(3- methoxybenzyl)amino]propyl}-3-phenylpropanamide 50 N-{(1S,2R)-1-(3,5- 429.3 difluorobenzyl)-3-[(2-furylmethyl)amino]-2- hydroxypropyl}-3- phenylpropanamide 51N-{(1S,2R)-1-(3,5- 460.2 difluorobenzyl)-2-hydroxy-3- [(2-methoxy-1-methylethyl)amino]propyl}-3- (1H-indol-1-yl)propanamide compound withmethyl hydroperoxide (1:2) 52 N-{(1S,2R)-1-(3,5- 446.3difluorobenzyl)-2-hydroxy-3- [(2-hydroxy-1- methylethyl)amino]propyl}-3-(1H-indol-1-yl)propanamide compound with methyl hydroperoxide (1:2) 53N-[(1S,2R)-3-(benzylamino)-1- 478.2 (3,5-difluorobenzyl)-2-hydroxypropyl]-3-(1H-indol-1- yl)propanamide compound with methylhydroperoxide (1:2) 54 N-{(1S,2R)-1-(3,5- 468.2 difluorobenzyl)-3-[(2-furylmethyl)amino]-2- hydroxypropyl}-3-(1H-indol-1- yl)propanamide 55N-[(1S,2R)-3- 443.3 [(cyclopropylmethyl)amino]-1-(3,5-difluorobenzyl)-2- hydroxypropyl]-3-(1H-indol-1- yl)propanamide 56N-{(1S,2R)-1-(3,5- 604 difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 3-(1H-indol-1-yl)propanamide 57N-{(1S,2R)-1-(3,5- 481.3 difluorobenzyl)-2-hydroxy-3- [(4-methylbenzyl)amino]propyl}-2- (4-isopropylphenyl)acetamide compound withmethyl hydroperoxide (1:1) 58 N-{(1S,2R)-1-(3,5- 449.3difluorobenzyl)-2-hydroxy-3- [(2-methoxy-1- methylethyl)amino]propyl}-2-(4-isopropylphenyl)acetamide 59 N-{(1S,2R)-1-(3,5- 435.3difluorobenzyl)-2-hydroxy-3- [(2-hydroxy-1- methylethyl)amino]propyl}-2-(4-isopropylphenyl)acetamide compound with methyl hydroperoxide (1:1) 60N-[(1S,2R)-3-(benzylamino)-1- 467.3 (3,5-difluorobenzyl)-2-hydroxypropyl]-2-(4- isopropylphenyl)acetamide compound with methylhydroperoxide (1:1) 61 N-{(1S,2R)-1-(3,5- 485.2difluorobenzyl)-2-hydroxy-3- [(4- methylbenzyl)amino]propyl}-2- [4-(methylthio)phenyl]acetamide compound with methyl hydroperoxide (1:1) 62N-{(1S,2R)-1-(3,5- 453.2 difluorobenzyl)-2-hydroxy-3- [(2-methoxy-1-methylethyl)amino]propyl}-2- [4- (methylthio)phenyl]acetamide 63N-{(1S,2R)-1-(3,5- 439.2 difluorobenzyl)-2-hydroxy-3- [(2-hydroxy-1-methylethyl)amino]propyl}-2- [4- (methylthio)phenyl]acetamide compoundwith methyl hydroperoxide (1:1) 64 N-[(1S,2R)-3-(benzylamino)-1- 471.2(3,5-difluorobenzyl)-2- hydroxypropyl]-2-[4-(methylthio)phenyl]acetamide compound with methyl hydroperoxide (1:1) 65N-{(1S,2R)-1-(3,5- 497.3 difluorobenzyl)-2-hydroxy-3- [(3-methoxybenzyl)amino]propyl}- 2-(4- isopropylphenyl)acetamide compoundwith methyl hydroperoxide (1:1) 66 N-[(1S,2R)-3-(butylamino)-1- 433(3,5-difluorobenzyl)-2- hydroxypropyl]-2-(4- isopropylphenyl)acetamidecompound with methyl hydroperoxide (1:1) 67 N-((1S,2R)-1-(3,5- 477.3difluorobenzyl)-3-{[2-(1,3- dioxolan-2-yl)ethyl]amino}-2-hydroxypropyl)-2-(4- isopropylphenyl)acetamide 68 N-{(1S,2R)-1-(3,5- 593difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}- 2-(4-isopropylphenyl)acetamide 69 N-{(1S,2R)-1-(3,5- 400.8difluorobenzyl)-2-hydroxy-3- [(3- methoxybenzyl)amino]propyl}- 2-[4-(methylthio)phenyl]acetamide compound with methyl hydroperoxide (1:1) 70N-{(1S,2R)-1-(3,5- 461.2 difluorobenzyl)-3-[(2- furylmethyl)amino]-2-hydroxypropyl}-2-[4- (methylthio)phenyl]acetamide 71N-[(1S,2R)-3-(butylamino)-1- 436.9 (3,5-difluorobenzyl)-2-hydroxypropyl]-2-[4- (methylthio)phenyl]acetamide compound with methylhydroperoxide (1:1) 72 N-((1S,2R)-1-(3,5- 481.2difluorobenzyl)-3-{[2-(1,3- dioxolan-2-yl)ethyl]amino}-2-hydroxypropyl)-2-[4- (methylthio)phenyl]acetamide 73 N-{(1S,2R)-1-(3,5-597 difluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}- 2-[4-(methylthio)phenyl]acetamide 74 3-[2-(benzyloxy)-4,6- 727.97dimethylphenyl]-N-{(1S,2R)-1- (3,5-difluorobenzyl)-2- hydroxy-3-[(3-iodobenzyl)amino]propyl}-3- methylbutanamide 752-[4-(benzyloxy)phenyl]-N- 657.33 {(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- [(3- iodobenzyl)amino]propyl}acetamide 76N-{(1S,2R)-1-(3,5- 583.79 difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 3-(2-fluorophenyl)propanamide 77N-{(1S,2R)-1-(3,5- 665.89 difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 4-(7-methoxy-2,3-dihydro-1-benzofuran-4-yl)-4- oxobutanamide 78 N-{(1S,2R)-1-(3,5- 553.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-[2-(dipropylamino)pyridin-4- yl]acetamide 79 N-{(1S,2R)-1-(3,5- 499difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(4-hydroxy- 3-methoxyphenyl)acetamide 80N-{(1S,2R)-1-(3,5- 469.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(3- hydroxyphenyl)acetamide 81 N-{(1S,2R)-1-(3,5- 513.3difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-(3,5-dimethoxyphenyl)acetamide 82 N-{(1S,2R)-1-(3,5- 525.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-thien-2- yl-1H-pyrazol-1-yl)acetamide 83N-{(1S,2R)-1-(3,5- 524.5 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-oxo-1,3- benzoxazol-3(2H)- yl)propanamide 843-(1H-benzimidazol-2-yl)-N- 523.3 {(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-hydroxypropanamide 85 N-{(1S,2R)-1-(3,5- 538.5 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-(4- morpholin-4-ylphenyl)acetamide 86 N-{(1S,2R)-1-(3,5- 542.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-(2-thioxo-1,3-benzothiazol-3(2H)- yl)acetamide 87 N-{(1S,2R)-1-(3,5- 536.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-3-(3-pyridin- 2-yl-1,2,4-oxadiazol-5- yl)propanamide 88N-{(1S,2R)-1-(3,5- 521.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-ethyl-1H- benzimidazol-1-yl)acetamide 89N-{(1S,2R)-1-(3,5- 525.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(5-hydroxy- 7-methyl[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)acetamide 90 N-{(1S,2R)-1-(3,5- 566.3difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-[(4-methyl- 4H-1,2,4-triazol-3-yl)thio]-2-phenylacetamide 91 N-{(1S,2R)-1-(3,5- 535.5 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-[5-(2-methylphenyl)-2H-tetraazol-2- yl]acetamide 923-(1,3-benzothiazol-2-yl)-N- 554.4 {(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-methoxypropanamide 93 1-acetyl-N-{(1S,2R)-1-(3,5- 550.5difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-phenylprolinamide 94 N-{(1S,2R)-1-(3,5- 523.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-(2-methyl-2,3-dihydro-1-benzofuran-5- yl)propanamide 95 N-{(1S,2R)-1-(3,5- 523.5difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-methyl-2- oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetamide 96 N-{(1S,2R)-1-(3,5- 551.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-(6-ethoxy-1H-benzimidazol-2- yl)propanamide 97 N-{(1S,2R)-1-(3,5- 536.5difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-4-(2,3-dihydro-1H-indol-1-yl)-4- oxobutanamide 98 N-{(1S,2R)-1-(3,5- 538.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(2-oxo-1,3- benzoxazol-3(2H)- yl)butanamide 99N-{(1S,2R)-1-(3,5- 521.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(5-phenyl- 1H-tetraazol-1-yl)acetamide 1002-[5-(1,3-benzodioxol-5-yl)- 565.4 2H-tetraazol-2-yl]-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}acetamide 101 2-(1H-1,2,3-benzotriazol-1- 550.5yl)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}hexanamide 102 3-(1,3-benzodioxol-5-yl)-N- 511.5{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}propanamide 103 N-{(1S,2R)-1-(3,5- 522.2difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(1,3-dioxo- 1,3-dihydro-2H-isoindol-2- yl)acetamide 104N-{(1S,2R)-1-(3,5- 536.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-3-(1,3-dioxo- 1,3-dihydro-2H-isoindol-2- yl)propanamide105 N-{(1S,2R)-1-(3,5- 495.5 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-4-oxo-4- phenylbutanamide 1062-(5-acetylthien-2-yl)-N- 501.4 {(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}acetamide 107 N-{(1S,2R)-1-(3,5-459.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-thien-2- ylacetamide 108 N-{(1S,2R)-1-(3,5- 555.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6- tetrahydro-7H-purin-7- yl)acetamide 109N-{(1S,2R)-1-(3,5- 511.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(3- hydroxyphenyl)-4- oxobutanamide 110N-{(1S,2R)-1-(3,5- 525.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(3- methoxyphenyl)-4- oxobutanamide 111N-{(1S,2R)-1-(3,5- 534.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(1H-indol-3- yl)-4-oxobutanamide 1122-(1-benzothien-4-yl)-N- 509.3 {(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}acetamide 113 N-{(1S,2R)-1-(3,5-555.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(1,3- dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-purin-9- yl)acetamide 114 N-{(1S,2R)-1-(3,5- 551.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-hydroxy-2-phenyl-2-thien-2-ylacetamide 115 N-{(1S,2R)-1-(3,5- 470.3difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-(1-oxidopyridin-3-yl)acetamide 116 2-(4-chloro-2-oxo-1,3- 560.3benzothiazol-3(2H)-yl)-N- {(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}acetamide 117 N-{(1S,2R)-1-(3,5-492.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(2,4- dihydroxy-1,3-thiazol-5- yl)acetamide 118N-{(1S,2R)-1-(3,5- 588.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-[2-(4- fluorophenyl)-1,3-benzoxazol- 5-yl]acetamide 119N-{(1S,2R)-1-(3,5- 571.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-pyridin- 4-yl-1,3-benzoxazol-5- yl)acetamide 120N-{(1S,2R)-1-(3,5- 508.5 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-methyl- 1,3-benzoxazol-5-yl)acetamide 1212-(2H-1,2,3-benzotriazol-2- 522.5 yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}butanamide122 N-{(1S,2R)-1-(3,5- 566.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2- yl)-2-hydroxybutanamide 1232-[2-(acetylamino)-1,3- 517.3 thiazol-4-yl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}acetamide 124 N-{(1S,2R)-1-(3,5- 537.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-pyridin- 2-yl-1,3-thiazol-4- yl)acetamide 125N-{(1S,2R)-1-(3,5- 588.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-{4- [(methylsulfonyl)amino]phenyl}- 4-oxobutanamide 126N-{(1S,2R)-1-(3,5- 560.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-3-{4- [(methylsulfonyl)amino]phenyl}propanamide 127N-{(1S,2R)-1-(3,5- 485.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-5-(1H-pyrazol- 1-yl)pentanamide 128 N-{(1S,2R)-1-(3,5-486.5 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-5-(1H-1,2,4- triazol-1-yl)pentanamide 129N-{(1S,2R)-1-(3,5- 536.1 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(1,3-dioxo- 1,3-dihydro-2H-isoindol-2- yl)propanamide130 N-{(1S,2R)-1-(3,5- 471.3 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-4-(1H- imidazol-1-yl)butanamide 131N-{(1S,2R)-1-(3,5- 487.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(2,6- dihydroxypyrimidin-4- yl)acetamide 132N-{(1S,2R)-1-(3,5- 543.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(3-fluoro-4- methoxyphenyl)-4- oxobutanamide 1333-(2-chlorophenyl)-2-cyano-N- 526.3 {(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}propanamide134 N-acetyl-N-{(1S,2R)-1-(3,5- 524.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-D- phenylalaninamide 135N-{(1S,2R)-1-(3,5- 509.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(4- methylphenyl)-4-oxobutanamide 136N-{(1S,2R)-1-(3,5- 525.5 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(2-hydroxy- 5-methylphenyl)-4- oxobutanamide 137N-{(1S,2R)-1-(3,5- 501.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-oxo-4-thien- 2-ylbutanamide 138 N-{(1S,2R)-1-(3,5-545.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-4-(2-naphthyl)-4-oxobutanamide 139 4-(1,3-benzodioxol-5-yl)-N- 525.5{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}butanamide 140 N-{(1S,2R)-1-(3,5- 550.5difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(3-pyridin- 2-yl-1,2,4-oxadiazol-5- yl)butanamide 141N-{(1S,2R)-1-(3,5- 565.5 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-3-[3-(4- methoxyphenyl)-1,2,4- oxadiazol-5-yl]propanamide142 N-{(1S,2R)-1-(3,5- 485.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-4-(2-furyl)-4- oxobutanamide 1434-(1,3-benzothiazol-2-yl)-N- 538.4 {(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}butanamide144 N-acetyl-4-chloro-N-{(1S,2R)- 558.3 1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}phenylalaninamide 1452-(acetylamino)-2-(1H-1,2,3- 551.4 benzotriazol-1-yl)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}acetamide 146 N-{(1S,2R)-1-(3,5- 561.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-ethyl-4H- [1,2,4]triazolo[1,5-a]benzimidazol-4-yl)acetamide 147 N-{(1S,2R)-1-(3,5- 472.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-methyl-2-(1H-1,2,4-triazol-1- yl)propanamide 148 N-{(1S,2R)-1-(3,5- 514.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-(5-pyrrolidin-1-yl-2H-tetraazol- 2-yl)acetamide 149 N-{(1S,2R)-1-(3,5-545.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-{[(methylamino)carbonyl]amino}- 3-thien-3-ylpropanamide 150N-{(1S,2R)-1-(3,5- 552.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-[1-methyl-3- (methylthio)-1H-indol-2- yl]acetamide 151N-{(1S,2R)-1-(3,5- 567.5 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(3,4- dihydro-2H-1,5-benzodioxepin-7-yl)-4-oxobutanamide 152 N-{(1S,2R)-1-(3,5- 554.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[(methoxyacetyl)amino]-3- phenylpropanamide 153 N-{(1S,2R)-1-(3,5- 552.5difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-[2-oxo-5-(trifluoromethyl)pyridin- 1(2H)-yl]propanamide 1542-cyano-N-{(1S,2R)-1-(3,5- 566.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-3-(3,4- dimethoxyphenyl)-2-methylpropanamide 155 4-(3,4-dichlorophenyl)-N- 563.3 {(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-4-oxobutanamide 156 N-{(1S,2R)-1-(3,5- 531.5 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-4-(3,4- difluorophenyl)-4-oxobutanamide 157 N-{(1S,2R)-1-(3,5- 545.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-4-(3,4- difluorophenyl)-2-methyl-4-oxobutanamide 158 N-{(1S,2R)-1-(3,5- 517.6 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-hydroxy-4-oxo-4-thien-2-ylbutanamide 159 N-{(1S,2R)-1-(3,5- 565.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(7-methoxy- 1-benzofuran-2-yl)-4- oxobutanamide 1604-dibenzo[b,d]furan-2-yl-N- 586.5 {(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-4-oxobutanamide 161 N-{(1S,2R)-1-(3,5- 547.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-(6-oxo-3- phenylpyridazin-1(6H)-yl)acetamide 162 2-(1H,1′H-2,2′-biimidazol-1- 509.4yl)-N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}acetamide 163 N-{(1S,2R)-1-(3,5- 551.5difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-4-(3,4-dihydro-2H-chromen-6-yl)-4- oxobutanamide 164 N-{(1S,2R)-1-(3,5- 526.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-oxo-1,2- benzisothiazol-2(3H)- yl)acetamide 1654-[2-(acetylamino)-4,5- 580.4 dimethylphenyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-4-oxobutanamide 166 N-{(1S,2R)-1-(3,5- 508.5 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-(3-oxo-2,3-dihydro-1H-isoindol-1- yl)acetamide 167 N-{(1S,2R)-1-(3,5- 511.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-4-(4-hydroxyphenyl)-4- oxobutanamide 168 N-{(1S,2R)-1-(3,5- 517.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-hydroxy-4-oxo-4-thien-3-ylbutanamide 169 N-{(1S,2R)-1-(3,5- 518.5difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-phenyl-2-(1H-pyrrol-1-yl)acetamide 170 4-(4-chloro-2-hydroxyphenyl)- 545.4N-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4- oxobutanamide 171 N-{(1S,2R)-1-(3,5- 536.5difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-(5-methyl-1,3-dioxo-1,3-dihydro-2H- isoindol-2-yl)acetamide 172 N-{(1S,2R)-1-(3,5-536.5 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(1-oxo-1,3- dihydro-2H-isoindol-2- yl)butanamide 173N-{(1S,2R)-1-(3,5- 536.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-methyl-2-(1- oxo-1,3-dihydro-2H-isoindol-2-yl)propanamide 174 N-{(1S,2R)-1-(3,5- 520.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-(1-methyl-1H-indol-3-yl)-2-oxoacetamide 175 N-{(1S,2R)-1-(3,5- 492.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-(2-thioxo-2,3-dihydro-1,3-thiazol-4- yl)acetamide 176 N-{(1S,2R)-1-(3,5- 532.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-2-[4-(1H-pyrrol-1- yl)phenyl]propanamide 177 2-(1-benzofuran-2-yl)-N- 521.4{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2- methylpropanamide 178 4-(1-benzofuran-2-yl)-N- 535.4{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4- oxobutanamide 179 N-{(1S,2R)-1-(3,5- 601.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(6-methoxy- 1,1′-biphenyl-3-yl)-4- oxobutanamide 1803-(3-chloroisoxazol-5-yl)-N- 492.4 {(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}propanamide181 N-{(1S,2R)-1-(3,5- 525.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-4-(4- methoxyphenyl)-4-oxobutanamide 182 N-{(1S,2R)-1-(3,5- 553.3 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-4-(2,3- dihydro-1,4-benzodioxin-6-yl)-4-oxobutanamide 183 N-{(1S,2R)-1-(3,5- 538.6 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-3-(2-oxo-2H- 1,3-benzoxazin-3(4H)-yl)propanamide 184 N-{(1S,2R)-1-(3,5- 510.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-(2-oxo-2,3-dihydro-1,3-benzoxazol-5- yl)acetamide 185 N-{(1S,2R)-1-(3,5- 509.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-oxo-2,3- dihydro-1H-benzimidazol-5- yl)acetamide 186N-{(1S,2R)-1-(3,5- 498.6 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-4-(5-methyl- 1H-pyrrol-2-yl)-4- oxobutanamide 187N-{(1S,2R)-1-(3,5- 522.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(5-pyridin- 2-yl-2H-tetraazol-2- yl)acetamide 188N-{(1S,2R)-1-(3,5- 523.5 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(5,7- dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)acetamide 189 N-{(1S,2R)-1-(3,5- 598.4difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-4-[5-(methylsulfinyl)-2,3-dihydro- 1H-indol-1-yl]-4- oxobutanamide 190N-{(1S,2R)-1-(3,5- 552.4 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-phenyl-2- (4H-1,2,4-triazol-3- ylthio)acetamide 191N-{(1S,2R)-1-(3,5- 514.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(5,6- dimethyl-2,4-dioxo-1,2,3,4- tetrahydropyridin-3-yl)acetamide 192 N-{(1S,2R)-1-(3,5- 540.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-3-(3-oxo-2,1- benzisothiazol-1(3H)-yl)propanamide 193 N-{(1S,2R)-1-(3,5- 535.5 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-3-phenyl-2- (1H-tetraazol-1-yl)propanamide 194 N-{(1S,2R)-1-(3,5- 535.4 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-[5-(4-methylphenyl)-2H-tetraazol-2- yl]acetamide 195 N-{(1S,2R)-1-(3,5- 483.2difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-hydroxy- 4-methylphenyl)acetamide 196N′-{(1S,2R)-1-(3,5- difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-phenyl-N,N- dipropylpentanediamide 197N-{(1S,2R)-1-(3,5- 453 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2- phenylacetamide 198 N-{(1S,2R)-1-(3,5- 530difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-fluoro-4- propoxyphenyl)acetamide 199N-{(1S,2R)-1-(3,5- 541.8 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-methoxy- 4-propoxyphenyl)acetamide 200N-{(1S,2R)-1-(3,5- 497.6 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(4- ethoxyphenyl)acetamide 201 N-{(1S,2R)-1-(3,5- 499.9difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-hydroxy- 4-methoxyphenyl)acetamide 202N-{(1S,2R)-1-(3,5- 469.3 difluorobenzyl)-2-hydroxy-3- [(3-methoxybenzyl)amino]propyl}- 3-phenylpropanamide 203 N-{(1S,2R)-1-(3,5-467.3 difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}-3-phenylpropanamide 204 N-{(1S,2R)-1-(3,5- 574.3 difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2- hydroxypropyl}-2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol- 2-yl]acetamide 2053-(1-butyl-1H-pyrazol-4-yl)- 513.3 N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- ethylbenzyl)amino]-2- hydroxypropyl}propanamide

Synthesis of N-(3-amino-2-hydroxy-propyl)-cycloalkyl andHeterocyclyl-alkylamides of Formula (I), Formula (Ic) and Formula (Id)Example 1 Synthesis of2-(4-butyl-2,3-dioxopiperazin-1-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}acetamideHydrochloride (206) Step A (4-Butyl-2,3-dioxo-piperazin-1-yl)-aceticAcid

N-butylethylenediamine (2.0 mL, 14 mmol) and diethyloxalate (2.1 mL, 15mmol) are added simultaneously to ice-cold iPrOH (30 mL) under nitrogen.The resultant solution is warmed to ambient temperature and then heatedto reflux for 6 hours. The mixture is then concentrated and purified byflash chromatography eluting with 0.10 MeOH:0.01 7N NH₃ in MeOH:0.89CH₂Cl₂ to give a white oily solid piperazine. This piperazine (2.4 g, 14mmol) is dissolved in dry DMF (25 mL), cooled to 0° C., and placed undernitrogen. Solid NaH (60% in mineral oil, 0.62 g, 16 mmol) is then addedand the resultant mixture stirred at ambient temperature for 0.5 hr. Themixture is placed back over ice and t-butylbromoacetate (2.3 mL, 16mmol) is slowly added. The resultant solution is stirred for an hour atambient temperature before it is quenched by the addition of brine anddiluted with EtOAc. The phases are separated and the organic phase isfurther extracted three times with brine, dried over Na₂SO₄, andconcentrated to give a yellow-orange oil. The product is isolated bycolumn chromatography eluting with 1:1 heptane:EtOAc with 1% of 7N NH₃in methanol to give the ester as a white crystalline solid (1.4 g, 5.0mmol, 36%) (M+H, 285.2). The ester is then converted to thecorresponding acid i by adding trifluoroacetic acid (6 mL) to an icecold solution of the ester (0.52 g, 2.0 mmol) in 10 mL of CH₂Cl₂. Afterstirring for two hours at ambient temperature, the reaction solution isconcentrated under high vacuum to give i.

Step B Synthesis of 206

A solution of i (0.12 g, 0.53 mmol), HATU (0.25 g, 0.66 mmol), and HOAT(0.09 g, 0.66 mmol) in 5 mL of dry DMF is stirred for an hour at ambienttemperature before a solution of[3-amino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(4-ethyl-benzyl)-carbamicacid benzyl ester (0.20 g, 0.40 mmol) and diisopropylethylamine (0.3 mL,1.7 mmol) in 5 mL of dry DMF is introduced. The resultant solution isstirred overnight at ambient temperature. The reaction solution is thenquenched with the addition of 1M HCl, diluted with EtOAc, and the phasesare separated. The organic is further extracted with 3× 1 M HCl, 3×saturated NaHCO₃, and 3× brine. The organic phase is then dried overNa₂SO₄, concentrated to an orange oil, and purified by columnchromatography eluting with 1:1 heptane:EtOAc to give the N-protectedproduct as a white solid (0.06 g, 0.09 mmol, 22%). The N-protectedproduct is then combined with 10% by weight palladium on activatedcarbon (0.015 g, 20 wt %) in 10 mL of methanol and placed under 4 psi ofH₂ for 3 hours. The reaction mixture is then filtered, concentrated, andpurified by column chromatography eluting with 0.04 MeOH:0.01 7N NH₃ inMeOH: 0.95 CH₂Cl₂ to afford 206 as the free base. The HCl salt isprepared by dissolving the free base in 1 mL of methanol and adding 2 mLof 7N methanolic HCl and concentrating the solution to give 206 as theHCl salt (0.03 g, 0.052 mmol, 60%) (M+H, 545.3).

Example 2 Synthesis of2-(4-ethyl-2,3-dioxopiperazin-1-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}acetamideHydrochloride (207) Step A (4-Ethyl-2,3-dioxo-piperazin-1-yl)-aceticAcid

To a solution of N-ethylpiperazin-2,3-dione (1.0 g, 7.0 mmol) in 10 mLof t-butanol over ice is added solid K₂CO₃ (1.1 g, 8.0 mmol). Afterstirring a few minutes t-butylbromoacetate (1.2 mL, 8.1 mmol) isintroduced dropwise. The resultant mixture is stirred overnight atambient temperature. The t-butanol is then azeotroped off withcyclohexane and the residue is partitioned between EtOAc and brine. Thephases are separated and the organic phase is extracted 2× 1M HCl, 2×saturated NaHCO₃, and 2× brine; dried over Na₂SO₄; and concentrated togive the ester as a white solid (0.35 g, 1.4 mmol, 19%). The ester isthen converted to the corresponding acid ii by adding trifluoroaceticacid (3 mL) to an ice cold solution of the ester (0.35 g, 1.4 mmol) in 5mL of CH₂Cl₂. After stirring for two hours at ambient temperature thereaction solution is concentrated under high vacuum to give H inquantitative yield.

Step B

A solution of ii (0.27 g, 1.3 mmol), HOBT (0.27 g, 2 mmol) and EDC (0.36g, 1.9 mmol) in 3 mL of dry DMF is stirred at ambient temperature for 45minutes. This solution is then added to a solution of[3-amino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(4-ethyl-benzyl)-carbamicacid benzyl ester (0.63 g, 1.3 mmol) and N-methylmorpholine (0.90 mL,8.2 mmol) in 3 mL of dry DMF. The resulting solution is then stirredovernight at ambient temperature at which time it is quenched by theaddition of saturated NaHCO₃ and diluted with EtOAc. The phases areseparated and the organic phase is further extracted 1× 1M HCl, 2×saturated NaHCO₃, and 2× brine; dried over Na₂SO₄; concentrated; andpurified by column chromatography eluting with 1:1 heptane:EtOAc (500mL) then 10% MeOH in CH₂Cl₂ to give the protected product. The free baseis then prepared by combining the protected product (0.17 g, 0.26 mmol)and Pearlman's catalyst (0.04 g, 20% by wt) in 15 mL of methanol andplacing the mixture under 5 psi of H₂ for 2.5 hours. The mixture is thenfiltered, run through a small plug of silica gel, and concentrated togive the free base 207. This is converted to the HCl salt 207 bydissolving the free base 207 in 1 mL of methanol, adding 2 mL of 7Nmethanolic HCl, and concentrating the solution to give 207 as a whitesolid (0.13 g, 0.21 mmol, 93%) (M+H, 517.26).

Example 3 Synthesis of2-(4-butyl-3-oxopiperazin-1-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}acetamideDihydrochloride (208) Step A 3-Oxo-piperazine-1-carboxylic AcidTert-butyl Ester

Oxopiperazine (3.38 g, 34 mmol) is dissolved in 20 mL of CH₂Cl₂. Et₃N(9.5 mL, 68 mmol) is added followed by Boc₂O (7.4 g, 34 mmol). Thesolution is allowed to stir at ambient temperature for 3 hours, at whichtime the reaction is quenched by the addition of brine. The phases areseparated and the organic phase is washed with brine, 1 M aqueous KH₂PO₄and dried over Na₂SO₄. The mixture is filtered and concentrated to giveiii as a white solid (6.1 g, 30 mmol, 90%). (MS: M+H, 199.0).

Step B 4-Butyl-3-oxo-piperazine-1-carboxylic Acid Tert-butyl Ester

A solution of oxopiperazine iii (6.1 g, 30 mmol) and n-butyl iodide (3.5mL, 31 mmol) in anhydrous DMF 60 mL) and anhydrous THF (20 mL) is addedto an ice cold suspension of sodium hydride (1.32 g, 33 mmol) in 20 mLof anhydrous DMF under a nitrogen atmosphere. The cold bath is removedand the mixture is stirred at ambient temperature for 5 h, at which timeit is quenched by the addition of brine and diluted with ethyl acetate.The phases are separated and the organic phase is washed with brine anddried over Na₂SO₄. The mixture is filtered and concentrated to give anoil which is purified by flash chromatography on a BIOTAGE 40 M columneluting with 100 mL heptane followed by Mar. 1, 1996:MeOH/7N NH₃ inMeOH/CH₂Cl₂ to give iv as a colorless oil (6.8 g, 27 mmol, 89%).(MS:M+H, 257.4).

Step C 1-Butyl-piperazin-2-one

Oxopiperazine iv is dissolved in 10 mL of CH₂Cl₂ under N₂ and 15 mL ofTFA is added. The solution is allowed to stir at ambient temperature for16 h. The solution is concentrated under reduced pressure, dissolved inwater, basified by the addition of solid NaOH, and extracted with ethylacetate. The combined extracts are dried over Na₂SO₄. The mixture isfiltered and concentrated to give v as an orange oil (3 g, 19 mmol,76%). (MS:M+H, 157.3).

Step D (4-Butyl-3-oxo-piperazin-1-yl)-acetic Acid Methyl Ester

Oxopiperazine v (0.4 g, 2.6 mmol) is combined with diisopropylethylamine(0.55 mL, 3.2 mmol) in 5 mL of methanol over ice, under N₂. Methylbromoacetate (0.27 mL, 2.9 mmol) is added dropwise and the solution isallowed to stir at ambient temperature for 2 hours, at which time it isquenched by the addition of 1 M KH₂PO₄ and diluted with ethyl acetate.The phases are separated and the organic phase is washed with 1 M KH₂PO₄and saturated aqueous NaHCO₃. The combined aqueous phases areback-extracted with ethyl acetate. The combined organic phases are driedover Na₂SO₄. The mixture is filtered and concentrated to give an oilwhich is purified by flash chromatography on a BIOTAGE 40S columneluting with 500 mL heptane followed by 1/1:heptane/EtOAc and9/1:CH₂Cl₂/MeOH to afford v as colorless oil (0.29 g, 1.3 mmol, 50%).(MS: M+H, 229.2).

Step E (4-Butyl-3-oxo-piperazin-1-yl)-acetic Acid

Oxopiperazine vi is dissolved in 5 mL of methanol and a suspension oflithium hydroxide monohydrate (0.3 g, 7.1 mmol) in 5 mL of water isadded. The mixture is allowed to stir at ambient temperature for 3 days.The mixture is concentrated under reduced pressure and suspended inwater. The mixture is treated with 10 mL acetic acid and extracted withEtOAc. The combined organic extracts are dried over Na₂SO₄. The mixtureis filtered and concentrated to provide vii as a colorless oil (0.15 g,0.7 mmol, 56%). (MS:M+H, 215.4)

Step F[3-[2-(4-Butyl-3-oxo-piperazin-1-yl)-acetylamino]-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(3-ethyl-benzyl)-carbamicAcid Benzyl Ester

Oxopiperazine vii (0.16 g, 0.75 mmol) is combined with HOAt (0.11 g,0.81 mmol) and HATU (0.31 g, 0.82 mmol) in 5 mL of dry DMF at 0° C.under N₂. After 0.5 h a solution of diisopropylethylamine (0.39 mL, 2.2mmol) and[3-amino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(4-ethyl-benzyl)-carbamicacid benzyl ester (0.38 g, 0.81 mmol) in 5 mL anhydrous DMF is added.The solution is allowed to stir for 16 h at ambient temperature. Thereaction is quenched by the addition of 1M HCl and diluted with ethylacetate. The phases are separated and the aqueous layer is extractedwith ethyl acetate. The combined organics are washed with 1M HCl,saturated aqueous NaHCO₃ and dried over Na₂SO₄. The mixture is filteredand concentrated to give an oil which is purified by flashchromatography on a BIOTAGE 40S column eluting with 400 mL of heptane,followed by 1 L of 2/1:heptane/EtOAC and 97/3:CH₂Cl₂/MeOH to give H as ayellow oil (0.2 g, 0.3 mmol, 40%). (MS:M+H, 665.3)

Step G 208

Oxopiperazine viii is dissolved in 10 mL of methanol and palladium (II)hydroxide (0.04 g) is added. The mixture is hydrogenated at 3 psi for 2hours, filtered and concentrated to give a colorless oil which ispurified by flash chromatography on a BIOTAGE 40S column eluting with97/3:CH₂Cl₂/MeOH followed by 97/3:CH₂Cl₂/MeOH and 90/9/1:CH₂Cl₂/MeOH/7NNH₃ in MeOH to give a colorless oil. The oil is dissolved in 3 mL MeOHand treated with 2 mL 1 N HCl in diether ether. The solvents are removedunder reduced pressure to give 208 as the bis HCl salt (0.030 g, 0.05mmol, 17%). (MS:M+H, 531.0).

Example 4 Synthesis of(2R)-2-(4-butyl-3-oxopiperazin-1-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}propanamide(209)

Compound 209 is prepared using the methods described above in Example 3with the substitution of methyl(s)-2-(trifluoromethylsulfonyloxy)propionate for methyl bromoacetate forthe synthesis of intermediate vi. (MS:M+H, 229.2).

Example 5 Synthesis of2-(1-butyl-2-oxo-1,2-dihydropyridin-4-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}acetamide(210) Step A 1-Butyl-4-methyl-1H-pyridin-2-one

A solution of 2-bromo-4-methylpyridine (7.25 g, 42.1 mmol) and1-iodobutane (5.8 mL, 50.6 mmol) is heated at 100° C. for 16 h. Theresidue is triturated with diethyl ether to provide a dark yellow gum.Ethyl alcohol (100 mL) is added followed by the addition of 1 N NaOH (50mL). The solution is allowed to stir for 4 h and NaOH (1.5 g) is added.After 2 h the solution is partitioned between ethyl acetate and H₂O andseparated. The aqueous phase is extracted with ethyl acetate and thecombined organics are washed with brine and dried over MgSO₄. Themixture is filtered and concentrated to give a dark oil which ispurified by flash chromatography (1/1:ethyl acetate/heptane) to provideix as a yellow oil (2.95 g, 34% 2 steps). (MS:M+H, 166.0).

Step B (1-Butyl-2-oxo-1,2-dihydro-pyridin-4-yl)-acetic Acid

A solution of pyridinone ix (1.7 g, 10.3 mmol) in 20 mL anhydrous THF isadded dropwise to a solution of LDA (2 M, 5.7 mL, 6.05 mmol) in 40 mLanhydrous THF at −78° C. The solution is allowed to stir for 45 minutesfollowed by the addition of solid CO₂ (10 g). After 0.5 h the mixture ispoured onto H₂O and acidified with 1 N HCl. The solution is concentratedunder reduced pressure and extracted with ethyl acetate and CH₂Cl₂. Thecombined organics are dried over MgSO₄, filtered and concentrated togive a solid which is purified by flash chromatography (9/1:CH₂Cl₂/MeOH)to provide x as a white solid (1.4 g, 66%). (MS: M+H, 210.0).

Compound 210 is prepared from x using procedures described above inExample 3. (MS:M+H, 526.2).

Example 6 Synthesis of2-(1-butyl-2-oxopiperidin-4-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}acetamide(211) Step A (1-Butyl-2-oxo-piperidin-4-yl)-acetic Acid

A mixture of pyridinone x (0.81 g, 3.9 mmol), palladium (II) hydroxide(0.84 g) and 15 mL of ethanol is hydrogenated at 33 psi for 4 days. Themixture is filtered to give xi as a colorless oil (0.83 g, 100%).(MS:M+H, 214.1).

Compound 211 is prepared from xi using procedures described above inExample 3 (36% yield). (MS:M+H, 530.1).

Example 7 Synthesis of2-(4-butyl-2,5-dioxopiperazin-1-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}acetamide(212) Step A[Benzyloxycarbonylmethyl-(2-tert-butoxycarbonylamino-acetyl)-amino]-aceticAcid Benzyl Ester

A solution of Boc-glycine (2 g, 11.4 mmol), DIPEA (4 mL, 22.8 mmol) andanhydrous DMF (20 mL) under N₂ is cooled with an ice bath. HATU (4.34 g,11.4 mL) and HOAt (1.55 g, 11.4 mL) are added and after 0.5 h amine R isadded. The ice bath is removed and the solution is allowed to stir for16 h. The solution is partitioned between ethyl acetate and 1 N HCl andseparated. The organic layer is washed with aqueous NaHCO₃, H₂O, brineand dried over MgSO₄. The mixture is filtered and concentrated to givexii as a light orange gum (5.05 g, 94%). (MS: M+H, 471.3).

Step B (2,5-Dioxo-piperazin-1-yl)-acetic Acid Benzyl Ester

Intermediate xii (4.8 g, 10.2 mmol) is added to a solution of anhydrousCH₂Cl₂ (10 mL) and TFA (10 mL) under N₂. After 2 h the solvents areremoved under reduced pressure and the residue is partitioned betweenCH₂Cl₂ and aqueous NaHCO₃ and separated. The organic layer is dried overMgSO₄, filtered and concentrated to give a solid that is triturated withheptane to give xiii as a tan solid (2.0 g, 75%). (MS: M+H, 263.1).

Step C (4-Butyl-2,5-dioxo-piperazin-1-yl)-acetic Acid Benzyl Ester

Dioxopiperazine xiii (1.0 g, 3.81 mmol) is added to a mixture of NaH(60%, 0.18 g, 4.57 mmol) in anhydrous DMF (20 mL) under N₂. The mixtureturns homogenous and 1-iodobutane (0.48 mL, 4.19 mmol) is added. After16 h the solution is partitioned between ethyl acetate and H₂O andseparated. The aqueous layer is extracted with ethyl acetate and thecombined organics are washed with H₂O, brine and dried over MgSO₄. Themixture is filtered and concentrated to give an oil which is purified byflash chromatography (CH₂Cl₂ followed by 98/2:CH₂Cl₂/MeOH) to give xivas a white solid (0.6 g, 50%). (MS: M+H, 319.3).

Step D (4-Butyl-2,5-dioxo-piperazin-1-yl)-acetic Acid

A mixture of dioxopiperazine xiv (0.4 g, 1.26 mmol), 10% Pd/C (0.025 g)and EtOH (10 mL) is hydrogenated at 20 psi for 8 h. The mixture isfiltered and concentrated to provide xv as an off-white solid (0.28 g,97%). (MS: M+H, 229.1).

Compound 212 is prepared from xv using procedures described above inExample 3. (MS:M+H, 545.2).

Example 8 Synthesis ofN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-oxo-4-propylcyclohexyl)acetamide(213) Step A 2-(3-Oxo-4-propyl-cyclohexyl)-malonic Acid Diethyl Ester

A solution of sodium metal (30 mg, 1.30 mmol) in absolute ethanol (4.0mL) is stirred at −10° C. for 0.5 h. Diethyl malonate (3.5 mL, 23 mmol)is added at −10° C. followed by addition of a solution of6-propyl-cyclohex-2-enone (3.0 g, 21.7 mmol) in absolute ethanol (3.0mL). The reaction mixture is stirred an additional 12 h at roomtemperature. The reaction mixture is then acidified to pH 3.0 with 10%hydrogen chloride solution and then extracted several times with diethylether. The combined ether extracts are washed with water, and saturatedsodium chloride, dried (sodium sulfate), filtered, and concentratedunder reduced pressure to yield a yellow oil. Purification by flashcolumn chromatography (silica, 83:17 hexanes/ethyl acetate) givesdiester xvi (5.07 g, 91%) as a light yellow oil: ¹H NMR (300 MHz, CDCl₃)δ 4.21 (q, J=7.0 Hz, 2H), 4.20 (q, J=7.0 Hz, 2H), 3.30 (s, 0.5H), 3.28(s, 0.5H), 2.67-1.55 (m, 8H), 1.43-1.11 (m, 10H), 0.90 (t, J=7.0 Hz,1.5H), 0.90 (t, J=7.0 Hz, 1.5H)

Step B (3-Oxo-cyclohexyl)-acetic Acid

A solution of diester xvi (2.37 g, 7.94 mmol) in 1 N potassium hydroxide(16.27 mL, 16.27 mmol) is heated at reflux for 2 h. The reaction iscooled to room temperature, diluted with water and extracted withmethylene chloride. The aqueous phase is acidified to pH 1-2 with 6 Nhydrogen chloride solution and then heated at reflux for 2 h. Thereaction is cooled to room temperature and extracted several times withmethylene chloride. The combined organic phase is washed with water,saturated sodium chloride, dried (sodium sulfate), filtered, andconcentrated under reduced pressure to yield a light yellow oil.Purification by flash column chromatography (silica, 2:1 hexanes/ethylacetate with 1% glacial acetic acid) gives carboxylic acid xvii (1.42 g,91%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 2.71-1.12 (m, 14H),1.11-0.82 (m, 3H); ESI MS m/z 197 [M−H]⁻.

Step C 213

To a stirred solution of acid xvii (244 mg, 1.23 mmol) andN,N-diisopropyl ethylamine (214 μL, 1.23 mmol) in methylene chloride(7.0 mL) is added HBTU (513 mg, 1.35 mmol) and the reaction mixturestirred for 0.5 h. To the above solution is added a solution of3-amino-4-(3,5-difluoro-phenyl)-1-(3-ethyl-benzylamino)-butan-2-ol (500mg, 1.35 mmol) (prepared according to the procedure found in U.S. patentapplication Ser. No. 09/895,871, filed Jun. 29, 2001) andN,N-diisopropylethylamine (428 μL, 2.46 mmol) in methylene chloride (7.0mL) and the reaction mixture is stirred under nitrogen for 18 h. Thereaction mixture is then diluted with additional methylene chloride andwashed with saturated sodium bicarbonate, 0.5 N hydrogen chloridesolution, saturated sodium chloride, dried (sodium sulfate), filtered,and concentrated under reduced pressure to yield an oily residue.Purification by flash column chromatography (silica, 7:93methanol/methylene chloride) gives 213 (360 mg, 33%) as a white solid:mp 52-54° C.; IR (ATR) 2960, 2932, 1698, 1627, 1596, 1533 cm⁻¹; ¹H NMR(500 MHz, CD₃OD) δ 7.33-7.30 (m, 2H), 7.25-7.21 (m, 2H), 6.85-6.82 (m,2H), 6.79-6.63 (m, 1H), 4.08-4.00 (m, 3H), 3.74-3.69 (m, 1H), 3.25-3.19(m, 1H), 3.06-2.95 (m, 1H), 2.87-2.83 (m, 1H), 2.69-2.64 (m, 2H),2.62-2.56 (m, 1H), 2.24-2.20 (m, 1H), 2.12-1.95 (m, 5H), 1.69-1.65 (m,2H), 1.37-1.32 (m, 8H), 1.16-1.08 (m, 2H), 0.92-0.88 (m, 3H); ESI MS m/z515 [C₃₀H₄₀F₂N₂O₃+H]⁺.

Example 9 Synthesis ofN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-oxocyclohexyl)acetamide(214) Step A 2-(3-Oxo-cyclohexyl)-malonic Acid Diethyl Ester

Diester xviii is prepared in 88% yield from cyclohex-2-enone by themethod described for the synthesis of diester xvi above: ¹H NMR (300MHz, CDCl₃) δ 4.44-4.12 (m, 4H), 2.88-1.22 (m, 16H).

Step B (3-Oxo-cyclohexyl)-acetic Acid

Acid xix is prepared in 70% yield from diester xviii by the methoddescribed for the synthesis of xvii above: ¹H NMR (300 MHz, CDCl₃) δ2.58-1.92 (m, 7H), 1.80-1.61 (m, 1H), 1.52-1.42 (m, 1H); ESI MS m/z 155[M−H]⁻.

Step C 214

214 is prepared in 23% yield from acid xix by the method described forthe synthesis of 213 (Step C) above: white solid; mp 139.5-149.8° C.; IR(ATR) 3313, 3258, 2940, 1702, 1627, 1595, 1541 cm⁻¹; ¹H NMR (500 MHz,DMSO-d₆) δ 7.78-7.74 (m, 1H), 7.22-6.89 (m, 7H), 4.95 (s, 1H), 3.95 (s,1H), 3.67 (s, 2H), 3.46 (s, 1H), 3.02-2.99 (m, 1H), 2.60-2.54 (m, 4H),2.20-2.12 (m, 3H), 1.93-1.82 (m, 5H), 1.54-1.36 (m, 2H), 1.18-1.08 (m,4H); ESI MS m/z 473 [C₂₇H₃₄F₂N₂O₃+H]⁺; Anal. Calcd for C₂₇H₃₄F₂N₂O₃: C,68.62; H, 7.28; N, 5.93. Found: C, 68.40; H, 7.06; N, 5.85.

Example 10 Synthesis of[3-Amino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(4-ethyl-benzyl)-carbamicAcid Benzyl Ester

To a solution of[1-(3,5-difluoro-benzyl)-3-(3-ethyl-benzylamino)-2-hydroxy-propyl]-carbamicacid tert-butyl ester (16.1 g, 37 mmol) and triethylamine (6.2 mL, 44mmol) in 80 mL of anhydrous THF under N₂ at 0° C. is addedbenzylchloroformate (5.8 mL, 41 mmol). The solution is warmed to ambienttemperature and stirred for 16 h. The solution is quenched with brineand concentrated to remove most of the THF. The residue is diluted withethyl acetate and separated. The organic phase is washed with 1 MKH₂PO₄, saturated NaHCO₃ and dried over Na₂SO₄. The mixture is filteredand concentrated to a white solid which is purified on a BIOTAGE 40Mcolumn eluting with 400 mL of heptane followed by 4/1:heptane/EtOAc toobtain[3-tert-butoxycarbonylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(3-ethyl-benzyl)-carbamicacid benzyl ester as a white solid (15 g, 26 mmol, 71%), (MS:M+H,569.4). This compound (6.0 g, 11 mmol) is dissolved in 10 mL ofanhydrous CH₂Cl₂ at 0° C. and 10 mL of TFA is added. The solution iswarmed to ambient temperature and stirred for 3 h. The solution isconcentrated, diluted with EtOAc and washed with 1M NaOH. The combinedorganics are dried (Na₂SO₄) and the mixture is filtered and concentratedto give desired compound as a white solid (5.0 g, 11 mmol, quant.yield), (MS:M+H, 469.5).

Example 11

The following compounds are prepared essentially according to theprocedure outlined in CHARTS 3A-E and set forth in Examples 1-10.

-   (a)    N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(ethoxymethyl)piperidin-1-yl]hexanamide    (compound 215);-   (b)    (2S)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(ethoxymethyl)piperidin-1-yl]hexanamide    (compound 216);-   (c)    N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(ethoxymethyl)piperidin-1-yl]pentanamide    (compound 217);-   (d)    (2S)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(ethoxymethyl)piperidin-1-yl]pentanamide    (compound 218);-   (e)    N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(ethoxymethyl)piperidin-1-yl]-4-(methylthio)butanamide    (compound 219);-   (f)    (2S)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(ethoxymethyl)piperidin-1-yl]-4-(methylthio)butanamide    (compound 220);-   (g)    2-(4-butyl-2-oxopiperazin-1-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}acetamide(compound    221);-   (h)    2-(4-butyl-2,3-dioxopiperazin-1-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}hexanamide(compound    222);-   (i)    (2S)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(2-methoxyethyl)piperidin-1-yl]-4-(methylthio)butanamide(compound    223);-   (j)    (2S)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(2-methoxyethyl)piperidin-1-yl]hexanamide(compound    224);-   (k)    (2S)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(2-methoxyethyl)piperidin-1-yl]pentanamide(compound    225);-   (l)    (2S)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(methylthio)-2-(4-propoxypiperidin-1-yl)butanamide(compound    226);-   (m)    (2S)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(4-propoxypiperidin-1-yl)hexanamide(compound    227);-   (n)    (2S)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(4-propoxypiperidin-1-yl)pentanamide(compound    228);-   (o)    2-(4-butyl-2,3-dioxopiperazin-1-yl)-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)hexanamide(compound    229);-   (p)    (2S)—N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-2-[4-(ethoxymethyl)piperidin-1-yl]-4-(methylthio)butanamide(compound    230);-   (q)    (2S)—N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-2-[4-(ethoxymethyl)piperidin-1-yl]hexanamide(compound    231);-   (r)    (2S)—N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-2-[4-(ethoxymethyl)piperidin-1-yl]pentanamide(compound    232); and-   (s)    N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(2,3-dioxo-4-pentylpiperazin-1-yl)acetamide(compound    233).

BIOLOGICAL EXAMPLES Example A Enzyme Inhibition Assay

The compounds of the invention are analyzed for inhibitory activity byuse of the MBP-C125 assay. This assay determines the relative inhibitionof beta-secretase cleavage of a model APP substrate, MBP-C125SW, by thecompounds assayed as compared with an untreated control. A detaileddescription of the assay parameters can be found, for example, in U.S.Pat. No. 5,942,400. Briefly, the substrate is a fusion peptide formed ofmaltose binding protein (MBP) and the carboxy terminal 125 amino acidsof APP-SW, the Swedish mutation. The beta-secretase enzyme is derivedfrom human brain tissue as described in Sinha et. al, 1999, Nature40:537-540) or recombinantly produced as the full-length enzyme (aminoacids 1-501), and can be prepared, for example, from 293 cellsexpressing the recombinant cDNA, as described in WO00/47618.

Inhibition of the enzyme is analyzed, for example, by immunoassay of theenzyme's cleavage products. One exemplary ELISA uses an anti-MBP captureantibody that is deposited on precoated and blocked 96-well high bindingplates, followed by incubation with diluted enzyme reaction supernatant,incubation with a specific reporter antibody, for example, biotinylatedanti-SW192 reporter antibody, and further incubation withstreptavidin/alkaline phosphatase. In the assay, cleavage of the intactMBP-C125SW fusion protein results in the generation of a truncatedamino-terminal fragment, exposing a new SW-192 antibody-positive epitopeat the carboxy terminus. Detection is effected by a fluorescentsubstrate signal on cleavage by the phosphatase. ELISA only detectscleavage following Leu 596 at the substrate's APP-SW 751 mutation site.

Specific Assay Procedure:

Compounds are diluted in a 1:1 dilution series to a six-pointconcentration curve (two wells per concentration) in one 96-plate rowper compound tested. Each of the test compounds is prepared in DMSO tomake up a 10 millimolar stock solution. The stock solution is seriallydiluted in DMSO to obtain a final compound concentration of 200micromolar at the high point of a 6-point dilution curve. Ten (10)microliters of each dilution is added to each of two wells on row C of acorresponding V-bottom plate to which 190 microliters of 52 millimolarNaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaOAc diluted compound plateis spun down to pellet precipitant and 20 microliters/well istransferred to a corresponding flat-bottom plate to which 30 microlitersof ice-cold enzyme-substrate mixture (2.5 microliters MBP-C125SWsubstrate, 0.03 microliters enzyme and 24.5 microliters ice cold 0.09%TX100 per 30 microliters) is added. The final reaction mixture of 200micromolar compound at the highest curve point is in 5% DMSO, 20millimolar NaAc, 0.06% TX100, at pH 4.5.

Warming the plates to 37 degrees C. starts the enzyme reaction. After 90minutes at 37 degrees C., 200 microliters/well cold specimen diluent isadded to stop the reaction and 20 microliters/well is transferred to acorresponding anti-MBP antibody coated ELISA plate for capture,containing 80 microliters/well specimen diluent. This reaction isincubated overnight at 4 degrees C. and the ELISA is developed the nextday after a 2 hours incubation with anti-192SW antibody, followed byStreptavidin-AP conjugate and fluorescent substrate. The signal is readon a fluorescent plate reader.

Relative compound inhibition potency is determined by calculating theconcentration of compound that showed a fifty percent reduction indetected signal (IC₅₀) compared to the enzyme reaction signal in thecontrol wells with no added compound. In this assay, the compounds ofthe invention exhibited an IC₅₀ of less than 50 micromolar.

Example B Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate

A synthetic APP substrate that can be cleaved by beta-secretase andhaving N-terminal biotin and made fluorescent by the covalent attachmentof oregon green at the Cys residue is used to assay beta-secretaseactivity in the presence or absence of the inhibitory compounds of theinvention. Useful substrates include the following:Biotin-SEVNL-DAEFR[oregon green]KK [SEQ ID NO: 1]Biotin-SEVKM-DAEFR[oregon green]KK [SEQ ID NO: 2]Biotin-GLNIKTEEISEISY-EVEFRC[oregon green]KK [SEQ ID NO: 3]Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF[oregon green]KK [SEQ ID NO:4]Biotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFFYTPKA[oregon green]KK [SEQ ID NO:5]

The enzyme (0.1 nanomolar) and test compounds (0.001-100 micromolar) areincubated in pre-blocked, low affinity, black plates (384 well) at 37degrees C. for 30 minutes. The reaction is initiated by addition of 150millimolar substrate to a final volume of 30 microliter per well. Thefinal assay conditions are: 0.001-100 micromolar compound inhibitor; 0.1molar sodium acetate (pH 4.5); 150 nanomolar substrate; 0.1 nanomolarsoluble beta-secretase; 0.001% Tween 20, and 2% DMSO. The assay mixtureis incubated for 3 hours at 37 degrees C., and the reaction isterminated by the addition of a saturating concentration of immunopurestreptavidin. After incubation with streptavidin at room temperature for15 minutes, fluorescence polarization is measured, for example, using aLJL Acqurest (Ex485 nm/Em530 nm). The activity of the beta-secretaseenzyme is detected by changes in the fluorescence polarization thatoccur when the substrate is cleaved by the enzyme. Incubation in thepresence or absence of compound inhibitor demonstrates specificinhibition of beta-secretase enzymatic cleavage of its synthetic APPsubstrate. In this assay, compounds of the invention exhibited an IC50of less than 50 micromolar.

Example C Beta-secretase Inhibition: P26-P4′SW Assay

Synthetic substrates containing the beta-secretase cleavage site of APPare used to assay beta-secretase activity, using the methods described,for example, in published PCT application WO00/47618. The P26-P4′SWsubstrate is a peptide of the sequence:(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF [SEQ ID NO: 6] The P26-P1standard has the sequence: (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL [SEQ IDNO: 7]

Briefly, the biotin-coupled synthetic substrates are incubated at aconcentration of from about 0 to about 200 micromolar in this assay.When testing inhibitory compounds, a substrate concentration of about1.0 micromolar is preferred. Test compounds diluted in DMSO are added tothe reaction mixture, with a final DMSO concentration of 5%. Controlsalso contain a final DMSO concentration of 5%. The concentration of betasecretase enzyme in the reaction is varied, to give productconcentrations with the linear range of the ELISA assay, about 125 to2000 picomolar, after dilution.

The reaction mixture also includes 20 millimolar sodium acetate, pH 4.5,0.06% Triton X100, and is incubated at 37 degrees C. for about 1 to 3hours. Samples are then diluted in assay buffer (for example, 145.4nanomolar sodium chloride, 9.51 millimolar sodium phosphate, 7.7millimolar sodium azide, 0.05% Triton X405, 6 g/liter bovine serumalbumin, pH 7.4) to quench the reaction, then diluted further forimmunoassay of the cleavage products.

Cleavage products can be assayed by ELISA. Diluted samples and standardsare incubated in assay plates coated with capture antibody, for example,SW192, for about 24 hours at 4 degrees C. After washing in TTBS buffer(150 millimolar sodium chloride, 25 millimolar Tris, 0.05% Tween 20, pH7.5), the samples are incubated with strepavidin-AP according to themanufacturer's instructions. After a one hour incubation at roomtemperature, the samples are washed in TTBS and incubated withfluorescent substrate solution A (31.2 g/liter2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5). Reaction withstreptavidin-alkaline phosphate permits detection by fluorescence.Compounds that are effective inhibitors of beta-secretase activitydemonstrate reduced cleavage of the substrate as compared to a control.

Example D Assays using Synthetic Oligopeptide-Substrates

Synthetic oligopeptides are prepared that incorporate the known cleavagesite of beta-secretase, and optionally detectable tags, such asfluorescent or chouromogenic moieties. Examples of such peptides, aswell as their production and detection methods are described in U.S.Pat. No. 5,942,400, herein incorporated by reference. Cleavage productscan be detected using high performance liquid chromatography, orfluorescent or chromogenic detection methods appropriate to the peptideto be detected, according to methods well known in the art.

By way of example, one such peptide has the sequence SEVNL-DAEF [SEQ IDNO: 8], and the cleavage site is between residues 5 and 6. Anotherpreferred substrate has the sequence ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF[SEQ ID NO: 9], and the cleavage site is between residues 26 and 27.

These synthetic APP substrates are incubated in the presence ofbeta-secretase under conditions sufficient to result in beta-secretasemediated cleavage of the substrate. Comparison of the cleavage resultsin the presence of the compound inhibitor to control results provides ameasure of the compound's inhibitory activity.

Example E Inhibition of Beta-Secretase Activity—Cellular Assay

An exemplary assay for the analysis of inhibition of beta-secretaseactivity utilizes the human embryonic kidney cell line HEKp293 (ATCCAccession No. CRL-1573) transfected with APP751 containing the naturallyoccurring double mutation Lys651Met52 to Asn651Leu652 (numbered forAPP751), commonly called the Swedish mutation and shown to overproduce Abeta (Citron et. al., 1992, Nature 360:672-674), as described in U.S.Pat. No. 5,604,102.

The cells are incubated in the presence/absence of the inhibitorycompound (diluted in DMSO) at the desired concentration, generally up to10 micrograms/ml. At the end of the treatment period, conditioned mediais analyzed for beta-secretase activity, for example, by analysis ofcleavage fragments. A beta can be analyzed by immunoassay, usingspecific detection antibodies. The enzymatic activity is measured in thepresence and absence of the compound inhibitors to demonstrate specificinhibition of beta-secretase mediated cleavage of APP substrate.

Example F Inhibition of Beta-Secretase in Animal Models of AD

Various animal models can be used to screen for inhibition ofbeta-secretase activity. Examples of animal models useful in theinvention include, but are not limited to, mouse, guinea pig, dog, andthe like. The animals used can be wild type, transgenic, or knockoutmodels. In addition, mammalian models can express mutations in APP, suchas APP695-SW and the like described herein. Examples of transgenicnon-human mammalian models are described in U.S. Pat. Nos. 5,604,102,5,912,410 and 5,811,633.

PDAPP mice, prepared as described in Games et. al., 1995, Nature373:523-527 are useful to analyze in vivo suppression of A beta releasein the presence of putative inhibitory compounds. As described in U.S.Pat. No. 6,191,166, 4 month old PDAPP mice are administered compoundformulated in vehicle, such as corn oil. The mice are dosed withcompound (1-30 mg/ml; preferably 1-10 mg/ml). After time, e.g., 3-10hours, the animals are sacrificed, and brains removed for analysis.

Transgenic animals are administered an amount of the compound inhibitorformulated in a carrier suitable for the chosen mode of administration.Control animals are untreated, treated with vehicle, or treated with aninactive compound. Administration can be acute, i.e., single dose ormultiple doses in one day, or can be chronic, i.e., dosing is repeateddaily for a period of days. Beginning at time 0, brain tissue orcerebral fluid is obtained from selected animals and analyzed for thepresence of APP cleavage peptides, including A beta, for example, byimmunoassay using specific antibodies for A beta detection. At the endof the test period, animals are sacrificed and brain tissue or cerebralfluid is analyzed for the presence of A beta and/or beta-amyloidplaques. The tissue is also analyzed for necrosis.

Animals administered the compound inhibitors of the invention areexpected to demonstrate reduced A beta in brain tissues or cerebralfluids and reduced beta amyloid plaques in brain tissue, as comparedwith non-treated controls.

Example G Inhibition of a Beta Production in Human Patients

Patients suffering from Alzheimer's Disease (AD) demonstrate anincreased amount of A beta in the brain. AD patients are administered anamount of the compound inhibitor formulated in a carrier suitable forthe chosen mode of administration. Administration is repeated daily forthe duration of the test period. Beginning on day 0, cognitive andmemory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; A beta depositsin the brain; amyloid plaque in the brain; and scores for cognitive andmemory function, as compared with control, non-treated patients.

Example H Prevention of A Beta Production in Patients at Risk for AD

Patients predisposed or at risk for developing AD are identified eitherby recognition of a familial inheritance pattern, for example, presenceof the Swedish Mutation, and/or by monitoring diagnostic parameters.Patients identified as predisposed or at risk for developing AD areadministered an amount of the compound inhibitor formulated in a carriersuitable for the chosen mode of administration. Administration isrepeated daily for the duration of the test period. Beginning on day 0,cognitive and memory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; amyloid plaque inthe brain; and scores for cognitive and memory function, as comparedwith control, non-treated patients. The invention and the manner andprocess of making and using it, are now described in such full, clear,concise and exact terms as to enable any person skilled in the art towhich it pertains, to make and use the same. It is to be understood thatthe foregoing describes preferred embodiments of the present inventionand that modifications may be made therein without departing from thespirit or scope of the present invention as set forth in the claims. Toparticularly point out and distinctly claim the subject matter regardedas invention, the following claims conclude this specification.

1. A compound of the formula:

and pharmaceutically acceptable salts thereof wherein m is 0-5; B isphenyl, pyridin-3-yl or the N-oxide of pyridine-3-yl, each of which isoptionally substituted with one, two, three or four groups independentlyselected from R₆, R′₆, R″₆ and R′″₆; R₄ and R₁₄ independently are H,—NRR′, —SR, —CN, —OCF₃, —CF₃, —CONRR′, —CO₂R, —SO₂NRR′,—O—P(═O)(OR)(OR′), —N(R)—C(═O) (R′), —N(R) (SO₂R′), —SO₂R, —C(═O)R,—NO₂, halogen, —(CH₂)₀₋₄-aryl, —(CH₂)₀₋₄-heteroaryl, or C₁-C₈ alkyl,C₂-C₇ alkenyl or C₂-C₇ alkynyl, each of which is optionally substitutedwith one, two or three groups selected from —NRR′, —SR, —CN, —OCF₃,—CF₃, —CONRR′, —CO₂R, —SO₂NRR′, —O—P(═O) (OR) (OR′), —N(R)—C(═O) (R′),—N(R) (SO₂R′)—SO₂R, —C(═O)R, —NO₂, halogen, —(CH₂)₀₋₄-aryl, and—(CH₂)₀₋₄-heteroaryl, or R₄ and R₁₄ together are oxo; R″₄ and R′″₄independently are H, —OR, —NRR′, —SR, —CN, —OCF₃, —CF₃, —CONRR′, —CO₂R,—SO₂NRR′, —O—P(═O)(OR)(OR′), —N(R)—C(═O) (R′), —N(R) (SO₂R′), —SO₂R,—C(═O)R, —NO₂, halogen, —(CH₂)₀₋₄-aryl, —(CH₂)₀₋₄-heteroaryl, or C₁-C₈alkyl, C₂-C₇ alkenyl or C₂-C₇ alkynyl, each of which is optionallysubstituted with one, two or three groups selected from —OR, —NRR′, —SR,—CN, —OCF₃, —CF₃, —CONRR′, —CO₂R, —SO₂NRR′, —O—P(═O) (OR) (OR′),—N(R)—C(═O) (R′), —N(R) (SO₂R′), —SO₂R, —C(═O)R, —NO₂, halogen,—(CH₂)₀₋₄-aryl, and —(CH₂)₀₋₄-heteroaryl, or R″₄ and R′″₄ together areoxo; R and R′ independently are —H, —(C₁-C₁₀) alkyl, —(CH₂)₀₋₄—R_(aryl),—(CH₂)₀₋₄—R_(heteroaryl), —(CH₂)₀₋₄—R_(heterocyclyl), or C₂-C₇ alkenylor C₂-C₇ alkynyl, each of which is optionally substituted with one, twoor three substituents selected from the group consisting of halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, mono- or dialkylamino, andC₁-C₆ alkyl, or —(CH₂)₀₋₄—C₃-C₇ cycloalkyl optionally substituted withone, two or three substituents selected from the group consisting ofhalogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, mono- ordialkylamino, and C₁-C₆ alkyl; R₁ is —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), orC₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independentlyselected from halogen, —OH, ═O, —SH, —C≡N, —CF₃, —C₁-C₃ alkoxy, amino,mono- or dialkylamino, —N(R)C(O)R′—, —OC(═O)-amino and —OC(═O)-mono- ordialkylamino, or C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which isoptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- ordialkylamino, or aryl, heteroaryl, heterocyclyl, —C₁-C₆ alkyl-aryl,—C₁-C₆ alkyl-heteroaryl, or —C₁-C₆ alkyl-heterocyclyl, where the ringportions of each are optionally substituted with 1, 2, 3, or 4 groupsindependently selected from halogen, —OH, —SH, —C≡N, —NR₁₀₅R′₁₀₅, —CO₂R,—N(R)COR′, or —N(R)SO₂R′, —C(═O)—(C₁-C₄) alkyl, —SO₂-amino, —SO₂-mono ordialkylamino, —C(═O)-amino, —C(═O)-mono or dialkylamino, —SO₂—(C₁-C₄)alkyl, or C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groupswhich are independently selected from halogen, or C₃-C₇ cycloalkyloptionally substituted with 1, 2, or 3 groups independently selectedfrom halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, —C₁-C₆ alkyland mono- or dialkylamino, or C₁-C₁₀ alkyl optionally substituted with1, 2, or 3 groups independently selected from halogen, —OH, —SH, —C≡N,—CF₃, —C₁-C₃ alkoxy, amino, mono- or dialkylamino and —C₁-C₃ alkyl, orC₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally substitutedwith 1, 2, or 3 groups independently selected from halogen, —OH, —SH,—C≡N, —CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino;and the heterocyclyl group is optionally further substituted with oxo;R₆, R′₆, R″₆, R′″₆, R_(6a), R_(6b), R′_(6a), R′_(6b), R″_(6a), R″_(6b),R′″_(6a) and R′″_(6b) independently are —OR, —NO₂, halogen, —CO₂R, —C≡N,—NRR′, —SR, —SO₂R, —C(═O)R, —OCF₃, —CF₃, —CONRR′, —SO₂NRR′, —O—P(═O)(OR) (OR′), —N(R) (COR′), —N(R) (SO₂R′), —(CH₂)₀₋₄—CO—NR₇R′ 7,—(CH₂)₀₋₄—O— (CH₂)₀₋₄—CONRR′, —(CH₂)₀₋₄—CO— (C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO— (C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO— (C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R_(aryl),—(CH₂)₀₋₄—R_(heteroaryl), —(CH₂)₀₋₄—R_(heterocyclyl),—(CH₂)₀₋₄—CO—R_(aryl), —(CH₂)₀₋₄—CO—R_(heteroaryl),—(CH₂)₀₋₄—CO—R_(heterocyclyl), —(CH₂)₀₋₄—CO—R₁₀, —(CH₂)₀₋₄—CO—O—R₁₁,—(CH₂)₀₋₄—SO₂—NR₇R′ 7, (CH₂)₀₋₄—SO— (C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂ (C₁-C₁₂alkyl), —(CH₂)₀₋₄—SO₂— (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(H orR₁₁)—CO—O—R₁₁, —(CH₂)₀₋₄—N(H or R₁₁)—CO—N(R₁₁)₂, —(CH₂)₀₋₄—N(H orR₁₁)—CS—N(R₁₁)₂, —(CH₂)₀₋₄—N(—H or R₁₁)—CO—R₇, —(CH₂)₀₋₄—NR₇R′ 7,—(CH₂)₀₋₄—R₁₀, —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R_(aryl))₂, —(CH₂)₀₋₄—O—CO—N(R₁₁)₂, —(CH₂)₀₋₄—O—CS—N(R₁₁)₂,—(CH₂)₀₋₄—O— (R₁₁), —(CH₂)₀₋₄—O—(R₁₁)—COOH, —(CH₂)₀₋₄—S— (R₁₁), C₃-C₇cycloalkyl, —(CH₂)₀₋₄—N(—H or R₁₁)—SO₂—R₇, or —(CH₂)₀₋₄—C₃-C₇cycloalkyl, or C₁-C₈ alkyl optionally substituted with one, two or threegroups independently selected from C₁-C₆ alkyl, —F, —Cl, —Br, —I, —OR,—NO₂, —F, —Cl, —Br, —I, —CO₂R, —C≡N, —NRR′, —SR, —SO₂R, —C(═O)R, —OCF₃,—CF₃, —CONRR′, —SO₂NRR′, —O—P(═O) (OR) (OR′), —N(R) (COR′), —N(R)(SO₂R′), —(CH₂)₀₋₄—CO—NR₇R′ 7, —(CH₂)₀₋₄—CO— (C₁-C₁₂ alkyl),—(CH₂)₀₋₄—CO— (C₂-C₁₂ alkenyl), —(CH₂)₀₋₄—CO— (C₂-C₁₂ alkynyl),—(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—R_(aryl),—(CH₂)₀₋₄—R_(heteroaryl), —(CH₂)₀₋₄—R_(heterocyclyl),—(CH₂)₀₋₄—CO—R_(aryl), —(CH₂)₀₋₄—CO—R_(heteroaryl),—(CH₂)₀₋₄—CO—R_(heterocyclyl), —(CH₂)₀₋₄—CO—R₁₀, —(CH₂)₀₋₄—CO—O—R₁₁,—(CH₂)₀₋₄—SO₂—NR₇R′₇, —(CH₂)₀₋₄—SO— (C₁-C₈ alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—SO₂— (C₃-C₇ cycloalkyl), —(CH₂)₀₋₄—N(H orR₁₁)—CO—O—R₁₁, —(CH₂)₀₋₄—N(H or R₁₁)—CO—N(R₁₁)₂, —(CH₂)₀₋₄—N(H orR₁₁)—CS—N(R₁₁₁)₂, —(CH₂)₀₋₄—N(—H or R₁₁)—CO—R₇, —(CH₂)₀₋₄—NR₇R′₇,—(CH₂)₀₋₄—R₁₀, —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P(O)—(O—R_(aryl))₂, —(CH₂)₀₋₄—O—CO—N(R₁₁)₂, —(CH₂)₀₋₄—O—CS—N(R₁₁)₂,—(CH₂)₀₋₄—O— (R₁₁), —(CH₂)₀₋₄—O— (R₁₁)—COOH, —(CH₂)₀₋₄—S—(R₁₁), C₃-C₇cycloalkyl, —(CH₂)₀₋₄—N(—H or R₁₁)—SO₂—R₇, or —(CH₂)₀₋₄—C₃-C₇cycloalkyl, or C₂-C₇ alkenyl or C₂-C₇ alkynyl, each of which isoptionally substituted with one, two or three groups independentlyselected from halogen or —OH, or C₂-C₇ alkenyl or C₂-C₇ alkynyl, each ofwhich is optionally substituted with one, two or three groupsindependently selected from halogen, C₁-C₃ alkyl, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, amino, and mono- or dialkylamino, or —(CH₂)₀₋₄—O—(C₁-C₆alkyl), where the alkyl portion is optionally substituted with one, two,three, four, or five of halogen, or any two of R_(6a), R_(6b), R′_(6a),R′_(6b), R″_(6a), R″_(6b), R′″_(6a) and R′″_(6b) together are oxo; R₇and R′₇ are the same or different and represent —H, —C₃-C₇ cycloalkyl,—(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),—C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆ alkyl chain with one double bondand one triple bond, or —C₁-C₆ alkyl optionally substituted with —OH or—NH₂; or; —C₁-C₆ alkyl optionally substituted with one, two or threegroups independently selected from halogen; or heterocyclyl optionallysubstituted with halogen, amino, mono- or dialkylamino, —OH, —C≡N,—SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₄ alkyl),—CO—NH₂, —CO—NH—C₁-C₆ alkyl, oxo and —CO—N(C₁-C₆ alkyl)₂; or C₁-C₆ alkyloptionally substituted with one, two or three groups independentlyselected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, and mono- or dialkylamino; or C₂-C₆ alkenyl or C₂-C₆ alkynyl,each of which is optionally substituted with one, two or three groupsindependently selected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or C₁-C₆ alkoxyoptionally substituted with one, two or three of halogen; aryl orheteroaryl, each of which is optionally substituted with halogen, amino,mono- or dialkylamino, —OH, —C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl,—SO₂—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₄ alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl,and —CO—N(C₁-C₆ alkyl)₂; or C₁-C₆ alkyl optionally substituted with one,two or three groups independently selected from C₁-C₃ alkyl, halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino; orC₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally substitutedwith one, two or three groups independently selected from C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- ordialkylamino; or C₁-C₆ alkoxy optionally substituted with one, two orthree of halogen; R₁₀ is heterocyclyl optionally substituted with one,two, three or four groups independently selected from C₁-C₆ alkyl; R₁₁is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,—(CH₂)₀₋₂—R_(aryl), or —(CH₂)₀₋₂—R_(heteroaryl); R_(aryl) is aryloptionally substituted with halogen, amino, mono- or dialkylamino, —OH,—C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆ alkyl)₂, —SO₂— (C₁-C₄alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl, or —CO—N(C₁-C₆ alkyl)₂; or C₁-C₆alkyl optionally substituted with one, two or three groups independentlyselected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, and mono- or dialkylamino; or C₂-C₆ alkenyl or C₂-C₆ alkynyl,each of which is optionally substituted with one, two or three groupsindependently selected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or C₁-C₆ alkoxyoptionally substituted with one, two or three of halogen; R_(heteroaryl)is heteroaryl, each of which is optionally substituted with halogen,amino, mono- or dialkylamino, —OH, —C≡N, —SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl,—SO₂—N(C₁-C₆ alkyl)₂, —SO₂—(C₁-C₄ alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl,or —CO—N(C₁-C₆ alkyl)₂; or C₁-C₆ alkyl optionally substituted with one,two or three groups independently selected from C₁-C₃ alkyl, halogen,—OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino; orC₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally substitutedwith one, two or three groups independently selected from C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- ordialkylamino; or C₁-C₆ alkoxy optionally substituted with one, two orthree of halogen; R_(heterocyclyl) is heterocyclyl optionallysubstituted with halogen, amino, mono- or dialkylamino, —OH, —C≡N,—SO₂—NH₂, —SO₂—NH—C₁-C₆ alkyl, —SO₂—N(C₁-C₆ alkyl)₂, —SO₂— (C₁-C₄alkyl), —CO—NH₂, —CO—NH—C₁-C₆ alkyl, ═O or —CO—N(C₁-C₆ alkyl)₂; or C₁-C₆alkyl optionally substituted with one, two or three groups independentlyselected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, and mono- or dialkylamino; or C₂-C₆ alkenyl or C₂-C₆ alkynyl,each of which is optionally substituted with one, two or three groupsindependently selected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃,C₁-C₃ alkoxy, amino, and mono- or dialkylamino; or C₁-C₆ alkoxyoptionally substituted with one, two or three of halogen; R₂ is —H; or—(CH₂)₀₋₄—R_(aryl) and —(CH₂)₀₋₄—R_(heteroaryl); or C₁-C₆ alkyloptionally substituted with one, two or three groups independentlyselected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, and mono- or dialkylamino; or C₂-C₆ alkenyl, C₂-C₆ alkynyl or—(CH₂)₀₋₄—C₃-C₇ cycloalkyl, each of which is optionally substituted withone, two or three groups independently selected from C₁-C₃ alkyl,halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy, amino, and mono- ordialkylamino; R₃ is —H, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—(CH₂)₀₋₄—R_(aryl), or —(CH₂)₀₋₄—R_(heteroaryl); or C₁-C₆ alkyloptionally substituted with one, two or three groups independentlyselected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, and mono- or dialkylamino; or (CH₂)₀₋₄—C₃-C₇ cycloalkyloptionally substituted with one, two or three groups independentlyselected from C₁-C₃ alkyl, halogen, —OH, —SH, —C≡N, —CF₃, C₁-C₃ alkoxy,amino, and mono- or dialkylamino; or R₂ and R₃ taken together with thecarbon atom to which they are attached form a carbocycle of three, four,five, six, or seven carbon atoms, where one atom is optionally aheteroatom selected from the group consisting of —O—, —S—, —SO₂—, and—NR₈—; R_(C) is hydrogen, —(CR₂₄₅R₂₅₀)₀₋₄-aryl,—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl, —(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl,—(CR₂₄₅R₂₅₀)₀₋₄-aryl-heteroaryl, —(CR₂₄₅R₂₅₀)₀₋₄-aryl-heterocyclyl,—(CR₂₄₅R₂₅₀)₀₋₄-aryl-aryl, —(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-aryl,—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heterocyclyl,—(CR₂₄₅R₂₅₀)₀₋₄-heteroaryl-heteroaryl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-heteroaryl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-heterocyclyl,—(CR₂₄₅R₂₅₀)₀₋₄-heterocyclyl-aryl, —[C(R₂₅₅) (R₂₆₀)]₁₋₃—CO—N—(R₂₅₅)₂,—CH (aryl)₂, —CH(heteroaryl)₂, —CH(heterocyclyl)₂,—CH(aryl)(heteroaryl), —(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH)— (CH₂)₀₋₁-aryl,—(CH₂)₀₋₁—CH((CH₂)₀₋₆—OH—(CH₂)₀₋₁-heteroaryl, —CH(-aryl or-heteroaryl)-CO—O(C₁-C₄ alkyl), —CH(—CH₂—OH)—CH(OH)-phenyl-NO₂, (C₁-C₆alkyl)-O— (C₁-C₆ alkyl)-OH; —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,—(CH₂)₀₋₆—C(═NR₂₃₅) (NR₂₃₅R₂₄₀), or C₁-C₁₀ alkyl optionally substitutedwith 1, 2, or 3 groups independently selected from the group consistingof R₂₀₅, —OC═ONR₂₃₅R₂₄₀, —S(═O)₀₋₂ (C₁-C₆ alkyl), —SH,—NR₂₃₅C═ONR₂₃₅R₂₄₀, —C═ONR₂₃₅R₂₄₀, and —S(═O)₂NR₂₃₅R₂₄₀, or—(CH₂)₀₋₃—(C₃-C₈) cycloalkyl wherein the cycloalkyl is optionallysubstituted with 1, 2, or 3 groups independently selected from the groupconsisting of R₂₀₅, —CO₂H, and —CO₂— (C₁-C₄ alkyl), or cyclopentyl,cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, orheterocyclyl wherein one, two or three carbons of the cyclopentyl,cyclohexyl, or cycloheptyl is optionally replaced with a heteroatomindependently selected from NH, NR₂₁₅, O, or S(═O)₀₋₂, and wherein thecyclopentyl, cyclohexyl, or cycloheptyl group can be optionallysubstituted with one or two groups that are independently R₂₀₅, ═O,—CO—NR₂₃₅R₂₄₀, or —SO₂— (C₁-C₄ alkyl), or C₂-C₁₀ alkenyl or C₂-C₁₀alkynyl, each of which is optionally substituted with 1, 2, or 3 R₂₀₅groups, wherein each aryl and heteroaryl is optionally substituted with1, 2, or 3 R₂₀₀, and wherein each heterocyclyl is optionally substitutedwith 1, 2, 3, or 4 R₂₁₀; R₂₀₀ at each occurrence is independentlyselected from —OH, —NO₂, halogen, —CO₂H, C≡N, —(CH₂)₀₋₄—CO—NR₂₂₀R₂₂₅,—(CH₂)₀₋₄—CO— (C₁-C₁₂ alkyl), —(CH₂)₀₋₄—CO— (C₂-C₁₂ alkenyl)—(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl), —(CH₂)₀₋₄—CO— (C₃-C₇ cycloalkyl),—(CH₂)₀₋₄—CO-aryl, —(CH₂)₀₋₄—CO-heteroaryl, —(CH₂)₀₋₄—CO-heterocyclyl,—(CH₂)₀₋₄—CO—O—R₂₁₅, —(CH₂)₀₋₄—SO₂—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—SO— (C₁-C₈alkyl), —(CH₂)₀₋₄—SO₂—(C₁-C₁₂ alkyl), —(CH₂)₀₋₄—SO₂— (C₃-C₇ cycloalkyl),—(CH₂)₀₋₄—N(H or R₂₁₅)—CO—O—R₂₁₅, —(CH₂)₀₋₄—N(H or R₂₁₅)—CO—N(R₂₁₅)₂,—(CH₂)₀₋₄—N—CS—N(R₂₁₅)₂, —(CH₂)₀₋₄—N(—H or R₂₁₅)—CO—R₂₂₀,—(CH₂)₀₋₄—NR₂₂₀R₂₂₅, —(CH₂)₀₋₄—O—CO— (C₁-C₆ alkyl), —(CH₂)₀₋₄—O—P (C)—(OR₂₄₀)₂, —(CH₂)₀₋₄—O—CO—N(R₂₁₅)₂, —(CH₂)₀₋₄—O—CS—N(R₂₁₅)₂, —(CH₂)₀₋₄—O—(R₂₁₅), —(CH₂)₀₋₄—O— (R₂₁₅)—COOH, —(CH₂)₀₋₄—S— (R₂₁₅), —(CH₂)₀₋₄—O—(C₁-C₆ alkyl optionally substituted with 1, 2, 3, or 5-F), C₃-C₇cycloalkyl, —(CH₂)₀₋₄—N(H or R₂₁₅)—SO₂—R₂₂₀, —(CH₂)₀₋₄—C₃-C₇ cycloalkyl,or C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₂₀₅ groups, orC₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl, each of which is optionallysubstituted with 1 or 2 R₂₀₅ groups, wherein the aryl and heteroarylgroups at each occurrence are optionally substituted with 1, 2, or 3groups that are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substitutedwith 1, 2, or 3 groups that are independently R₂₀₅ or R₂₁₀, and whereinthe heterocyclyl group at each occurrence is optionally substituted with1, 2, or 3 groups that are independently R₂₁₀; R₂₀₅ at each occurrenceis independently selected from C₁-C₆ alkyl, halogen, —OH, —O-phenyl,—SH, —C≡N, —CF₃, C₁-C₆ alkoxy, NH₂, NH(C₁-C₆ alkyl) or N—(C₁-C₆ alkyl)(C₁-C₆ alkyl); R₂₁₀ at each occurrence is independently selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, —NR₂₂₀R₂₂₅, OH, C≡N, —CO—(C₁-C₄ alkyl), —SO₂—NR₂₃₅R₂₄₀, —CO—NR₂₃₅R₂₄₀, —SO₂—(C₁-C₄ alkyl), ═O, orC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₇ cycloalkyl, each ofwhich is optionally substituted with 1, 2, or 3 R₂₀₅ groups; R₂₁₅ ateach occurrence is independently selected from C₁-C₆ alkyl,—(CH₂)₀₋₂-(aryl), C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, and—(CH₂)₀₋₂-(heteroaryl), —(CH₂)₀₋₂-(heterocyclyl), wherein the aryl groupat each occurrence is optionally substituted with 1, 2, or 3 groups thatare independently R₂₀₅ or R₂₁₀, and wherein the heterocyclyl andheteroaryl groups at each occurrence are optionally substituted with 1,2, or 3 R₂₁₀; R₂₂₀ and R₂₂₅ at each occurrence are independentlyselected from —H, —C₃-C₇ cycloalkyl, —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),—(C₁-C₆ alkyl)-O— (C₁-C₃ alkyl), —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —C₁-C₆alkyl chain with one double bond and one triple bond, -aryl,-heteroaryl, and -heterocyclyl, or —C₁-C₁₀ alkyl optionally substitutedwith —OH, —NH₂ or halogen, wherein the aryl, heterocyclyl and heteroarylgroups at each occurrence are optionally substituted with 1, 2, or 3R₂₇₀ groups R₂₃₅ and R₂₄₀ at each occurrence are independently H, orC₁-C₆ alkyl; R₂₄₅ and R₂₅₀ at each occurrence are independently selectedfrom —H, C₁-C₄ alkyl, C₁-C₄ alkylaryl, C₁-C₄ alkylheteroaryl, C₁-C₄hydroxyalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —(CH₂)₀₋₄—C₃-C₇cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and phenyl; or R₂₄₅ and R₂₅₀are taken together with the carbon to which they are attached to form acarbocycle of 3, 4, 5, 6, or 7 carbon atoms, where one carbon atom isoptionally replaced by a heteroatom selected from —O—, —S—, —SO₂—, and—NR₂₂₀—; R₂₅₅ and R₂₆₀ at each occurrence are independently selectedfrom —H, —(CH₂)₁₋₂—S(O)₀₋₂—(C₁-C₆ alkyl), —(C₁-C₄ alkyl)-aryl, —(C₁-C₄alkyl)-heteroaryl, —(C₁-C₄ alkyl)-heterocyclyl, -aryl, -heteroaryl,-heterocyclyl, —(CH₂)₁₋₄—R₂₆₅— (CH₂)₀₋₄-aryl, —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heteroaryl, —(CH₂)₁₋₄—R₂₆₅—(CH₂)₀₋₄-heterocyclyl, or C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, eachof which is optionally substituted with 1, 2, or 3 R₂₀₅ groups, whereineach aryl or phenyl is optionally substituted with 1, 2, or 3 groupsthat are independently R₂₀₅, R₂₁₀, or C₁-C₆ alkyl substituted with 1, 2,or 3 groups that are independently R₂₀₅ or R₂₁₀, and wherein eachheterocyclyl is optionally substituted with 1, 2, 3, or 4 R₂₁₀; R₂₆₅ ateach occurrence is independently —O—, —S— or —N(C₁-C₆ alkyl)-; R₂₇₀ ateach occurrence is independently R₂₀₅, halogen C₁-C₆ alkoxy, C₁-C₆haloalkoxy, NR₂₃₅R₂₄₀, —OH, —C≡N, —CO— (C₁-C₄ alkyl), SO₂—NR₂₃₅R₂₄₀,—CO—NR₂₃₅R₂₄₀, —SO₂— (C₁-C₄ alkyl), ═O, or C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl or —(CH₂)₀₋₄—C₃-C₇ cycloalkyl, each of which is optionallysubstituted with 1, 2, or 3 R₂₀₅ groups.
 2. A compound according toclaim 1 wherein B is phenyl optionally substituted with one, two, threeor four groups independently selected from R₆, R′₆, R″₆ and R′″₆.
 3. Acompound according to claim 2 wherein R₂ and R₃ are hydrogen; R₁ is—C₁-C₃ alkyl-aryl, the aryl optionally substituted with one or twogroups independently selected from halogen; and R_(c) is —C₁-C₃alkyl-aryl, where the aryl is optionally substituted with halogen or—C₁-C₆ alkyl.
 4. A compound according to claim 3 wherein m is 0; R₄ andR′₄ are hydrogen; R₁ is phenylmethyl, where the phenyl is optionallysubstituted with one or two groups independently selected from halogen;R₂ and R₃ are hydrogen; and R₁ is phenylmethyl, where the phenyl isoptionally substituted with halogen or —C₁-C₆ alkyl.
 5. A compoundaccording to claim 1 which is selected fromN-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(4-fluorophenyl)-4-oxobutanamide;N-{(1S,2R)-1-benzyl-3-[(2,3-dimethylcyclohexyl)amino]-2-hydroxypropyl}-3-phenylbutanamide;N-((1S,2R)-1-benzyl-3-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-2-hydroxypropyl)-2-phenylbutanamide;N-((1S,2R)-1-benzyl-3-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-2-hydroxypropyl)-3-phenylbutanamide;N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(1-phenylethyl)amino]propyl}-3-phenylbutanamide;N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(1,2,2-trimethylpropyl)amino]propyl}-2-phenylbutanamide;N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(1,2,2-trimethylpropyl)amino]propyl}-3-phenylbutanamide;N-{(1S,2R)-1-benzyl-3-[(1,3-dimethylbutyl)amino]-2-hydroxypropyl}-2-phenylbutanamide;N-{(1S,2R)-1-benzyl-3-[(1,3-dimethylbutyl)amino]-2-hydroxypropyl}-3-phenylbutanamide;N-{(1S,2R)-1-benzyl-3-[(1-ethylpropyl)amino]-2-hydroxypropyl}-2-phenylbutanamide;N-{(1S,2R)-1-benzyl-3-[(1-ethylpropyl)amino]-2-hydroxypropyl}-3-phenylbutanamide;2-[4-(2-amino-2-oxoethoxy)phenyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[4-(2-oxo-2-pyrrolidin-1-ylethoxy)phenyl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-{4-[(methylsulfonyl)amino]phenyl}acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}acetamide;2-[3-(2-amino-2-oxoethoxy)phenyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-hydroxy-4-phenoxy-3-phenylbutanamide;2-(1,1′-biphenyl-4-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}butanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-(4-phenoxyphenyl)butanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-(4-phenoxyphenyl)acetamide;2-[3-chloro-4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-(2,4-dimethylphenyl)-4-oxobutanamide;4′-[4-({(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}amino)-4-oxobutanoyl]-1,1′-biphenyl-2-carboxamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-{2-[(methylsulfonyl)amino]phenyl}-4-oxobutanamide;(2Z)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-phenyl-3-pyridin-4-ylprop-2-enamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[4-(1,3-dihydro-2H-isoindol-2-yl)phenyl]propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-(2,3-dihydro-1H-inden-5-yl)butanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-4-phenylbutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-(4-hydroxy-5-isopropyl-2-methylphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[4-(2-methylprop-1-enyl)phenyl]propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[4-(thien-2-ylcarbonyl)phenyl]propanamide;(2R)—N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-(6-methoxy-2-naphthyl)propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[4-(2-oxopyrrolidin-1-yl)phenyl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-(3,4-dihydronaphthalen-1-yl)butanamide;N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-(4-isopropylphenyl)acetamide;N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[4-(methylthio)phenyl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(pyridin-2-ylmethyl)amino]propyl}-3-phenylpropanamideN-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxy-1-methylethyl)amino]propyl}-3-phenylpropanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-1-methylethyl)amino]propyl}-3-phenylpropanamide;N-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-phenylpropanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-phenylpropanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-furylmethyl)amino]-2-hydroxypropyl}-3-phenylpropanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-1-methylethyl)amino]propyl}-3-(1H-indol-1-yl)propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(4-methylbenzyl)amino]propyl}-2-(4-isopropylphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxy-1-methylethyl)amino]propyl}-2-(4-isopropylphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-1-methylethyl)amino]propyl}-2-(4-isopropylphenyl)acetamide;N-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-(4-isopropylphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(4-methylbenzyl)amino]propyl}-2-[4-(methylthio)phenyl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxy-1-methylethyl)amino]propyl}-2-[4-(methylthio)phenyl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-1-methylethyl)amino]propyl}-2-[4-(methylthio)phenyl]acetamide;N-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-[4-(methylthio)phenyl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-(4-isopropylphenyl)acetamide;N-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-(4-isopropylphenyl)acetamide;N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-2-hydroxypropyl)-2-(4-isopropylphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-(4-isopropylphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[4-(methylthio)phenyl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-furylmethyl)amino]-2-hydroxypropyl}-2-[4-(methylthio)phenyl]acetamide;N-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-[4-(methylthio)phenyl]acetamide;N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-2-hydroxypropyl)-2-[4-(methylthio)phenyl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[4-(methylthio)phenyl]acetamide;3-[2-(benzyloxy)-4,6-dimethylphenyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-methylbutanamide;2-[4-(benzyloxy)phenyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-(2-fluorophenyl)propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-(7-methoxy-2,3-dihydro-1-benzofuran-4-yl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[2-(dipropylamino)pyridin-4-yl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(4-hydroxy-3-methoxyphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-hydroxyphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3,5-dimethoxyphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-oxo-1,3-benzoxazol-3(2H)-yl)propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(4-morpholin-4-ylphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-2-phenylacetamide;1-acetyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-phenylprolinamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(5-phenyl-1H-tetraazol-1-yl)acetamide;3-(1,3-benzodioxol-5-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-oxo-4-phenylbutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(3-hydroxyphenyl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(3-methoxyphenyl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(1H-indol-3-yl)-4-oxobutanamide;2-(1-benzothien-4-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-hydroxy-2-phenyl-2-thien-2-ylacetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(1-oxidopyridin-3-yl)acetamide;2-(4-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-pyridin-4-yl-1,3-benzoxazol-5-yl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-methyl-1,3-benzoxazol-5-yl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-{4-[(methylsulfonyl)amino]phenyl}-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{4-[(methylsulfonyl)amino]phenyl}propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(3-fluoro-4-methoxyphenyl)-4-oxobutanamide;3-(2-chlorophenyl)-2-cyano-N-{(1S,2R)-1-(3,5-difluorobenzyl}-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl)propanamide;N-acetyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-D-phenylalaninamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(4-methylphenyl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(2-hydroxy-5-methylphenyl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(2-naphthyl)-4-oxobutanamide;4-(1,3-benzodioxol-5-yl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}butanamide;N-acetyl-4-chloro-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}phenylalaninamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl}-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl)-3-[(methoxyacetyl)amino]-3-phenylpropanamide;2-cyano-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(3,4-dimethoxyphenyl)-2-methylpropanamide;4-(3,4-dichlorophenyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(3,4-difluorophenyl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(3,4-difluorophenyl)-2-methyl-4-oxobutanamide;4-dibenzo[b,d]furan-2-yl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(3,4-dihydro-2H-chromen-6-yl)-4-oxobutanamide;4-[2-(acetylamino)-4,5-dimethylphenyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(4-hydroxyphenyl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-phenyl-2-(1H-pyrrol-1-yl)acetamide;4-(4-chloro-2-hydroxyphenyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[4-(1H-pyrrol-1-yl)phenyl]propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(6-methoxy-1,1′-biphenyl-3-yl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(4-methoxyphenyl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-oxobutanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-phenyl-2-(4H-1,2,4-triazol-3-ylthio)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-phenyl-2-(1H-tetraazol-1-yl)propanamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-hydroxy-4-methylphenyl)acetamide;N′-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-phenyl-N,N-dipropylpentanediamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-phenylacetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-fluoro-4-propoxyphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-methoxy-4-propoxyphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(4-ethoxyphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-hydroxy-4-methoxyphenyl)acetamide;N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-phenylpropanamide;andN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-phenylpropanamide.6. A method of treating a patient who has, or in preventing a patientfrom getting, a disease or condition selected from the group consistingof Alzheimer's disease, for helping prevent or delay the onset ofAlzheimer's disease, for treating patients with mild cognitiveimpairment (MCI), for treating Down's syndrome, for treating humans whohave Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type,for treating cerebral amyloid angiopathy, for treating otherdegenerative dementias, diffuse Lewy body type of Alzheimer's diseaseand who is in need of such treatment which comprises administration of atherapeutically effective amount of a compound of claim
 1. 7. A methodof treatment according to claim 1 where the therapeutically effectiveamount for oral administration is from about 0.1 mg/day to about 1,000mg/day; for parenteral, sublingual, intranasal, intrathecaladministration is from about 0.5 to about 100 mg/day; for depoadministration and implants is from about 0.5 mg/day to about 50 mg/day;for topical administration is from about 0.5 mg/day to about 200 mg/day;for rectal administration is from about 0.5 mg to about 500 mg.